Ttp phosphorylation for the identification of personalized medicines

ABSTRACT

The present invention relates to a method of determining if a patient is likely to respond to a treatment with a targeted therapy compound selected from protein kinase inhibitors, small molecule inhibitors, and monoclonal antibody-based compounds. The present invention further relates to a method of identifying a targeted therapy compound selected from protein kinase inhibitors, small molecule inhibitors, and monoclonal antibody-based compounds for personalized medicine. The present invention also relates to a method of treatment of cancer in a patient. The present invention also relates to a targeted therapy compound selected from protein kinase inhibitors, small molecule inhibitors, and monoclonal antibody-based compounds for use in a method of treatment of cancer in a patient.

CROSS REFERENCE TO A RELATED APPLICATION

This application is a Divisional Application of U.S. Application SerialNo. 16/710,455, filed Dec. 11, 2019, which is incorporated herein byreference in its entirety.

The Sequence Listing for this application is labeled“SeqList-08Mar23.xml ”, which was created on Mar. 8, 2023 and is 3 KB.The entire content is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method of determining if a patient islikely to respond to a treatment with a targeted therapy compoundselected from protein kinase inhibitors, small molecule inhibitors, andmonoclonal antibody-based compounds. The present invention furtherrelates to a method of identifying a targeted therapy compound selectedfrom protein kinase inhibitors, small molecule inhibitors, andmonoclonal antibody-based compounds for personalized medicine. Thepresent invention also relates to a method of treatment of cancer in apatient. The present invention also relates to a targeted therapycompound selected from protein kinase inhibitors, small moleculeinhibitors, and monoclonal antibody-based compounds for use in a methodof treatment of cancer in a patient.

BACKGROUND OF THE INVENTION

A key RNA-binding protein that promotes AU-rich mRNA deadenylation anddecay is the zinc finger protein, tristetraprolin (TTP/ZFP36). Manyhuman tumors are found to be associated with deficiency of TTP, which islinked to hallmarks of cancer. The aberrant expression or activity ofTTP/ZFP36 could be attributed to changes at different levels ofregulation, including transcriptional (e.g. epigenetic),post-transcriptional, and post-translational regulation.

Phosphorylation of TTP/ZFP36 by various protein kinases is one of theposttranslational modifications that profoundly affect its cellularlocalization and activity [1], [2], [3]. For example, the p38/MK2 is apathway that leads to TTP phosphorylation preventing its ability torecruit mRNA decay machinery and subsequently leading to over-productionof ARE-mRNA products.

Protein phosphorylation and dephosphorylation events are mediatedthrough the action of protein kinases. Protein phosphorylation bykinases is a post-translational mechanism that affects numerous cellularresponses to stimuli and influences downstream transcriptional andpost-transcriptional events. Human cells contain hundreds of kinases,many of which can be aberrantly active in cancer cells. Kinase activitycan cause abnormal regulation of gene expression at different levels.

Phosphorylation of proteins by different protein kinases is a mechanismof post-translational modification that highly affects the cellularlocalization and activity of the proteins. Protein phosphorylationresults in alteration of protein structure and conformation, andmodifies its activity and function. The commonly phosphorylated aminoacids in eukaryotes are serine, threonine, and tyrosine. Thephosphorylation is mediated through the action of a protein kinase (PK),and can be reverse through the action of a phosphatase. Nearly 2% of thehuman genome encode for PKs, representing about 538 genes which aresubdivided into typical, or conventional, and atypical protein kinases,according to the kinase database (http://kinase.com/kinbase/). Themajority of typical PKs phosphorylates serine/threonine (STPKs) and onlya minority of PKs phosphorylates tyrosine, and atypical PKs are mostlySTPKs. To date, FDA has approved 37 small molecule kinase inhibitors andmany others are in phase-⅔ clinical trials. Most of the approved kinasedrugs are intended for treatment of cancers, and only few of them havebeen approved for treatment of non-cancerous conditions, such assirolimus for organ rejection.

Previous reports indicate that phosphorylation events duringinflammation lead to stabilization of TTP/ZFP36 and thatde-phosphorylated TTP is unstable and less abundant in cells [1],[2].Unlike the active unphosphorylated TTP/ZFP36, MK2- phosphorylated TTP isof increased abundance due to protein stabilization, and is less active.

It has been shown that TTP/ZFP36 has multiple phosphorylation sites, andthus can be affected by several signaling pathways and many kinases [4].For example, major MK2 sites for TTP/ZFP36 phosphorylation aremouse/human serine 52/60 and 178/186. However, there are many otherpotential amino acid sites for phosphorylation and for a variety ofkinase targets.

Due to high occurrence of side effects associated with various drugs, itis important to assess, prior to an administration of a drug, whether atreatment with a certain drug is likely to be successful. Personalizedmedicine allows for customizing the specific treatment to a patient’sneeds, i.e. the patient’s genetic and phenotypical features, and thusallows for targeted therapy of a patient. There is an urgent need forsuitable biomarkers for assessing whether a patient is likely to respondto a drug. For example, there is the urgent need for biomarkers that arecapable of indicating whether a targeted therapy compound selected fromprotein kinase inhibitors, small molecule inhibitors, and monoclonalantibody-based compounds effectively evokes a therapeutic effect. Thepresent invention thus aims at providing a universal biomarker fordetermining whether a patient is likely to respond to a treatment, andfor selecting an appropriate drug for a patient. The present inventionfurther aims at providing a method of treatment of cancer, and atargeted therapy compound selected from protein kinase inhibitors, smallmolecule inhibitors, and monoclonal antibody-based compounds for use ina method of treatment of cancer.

SUMMARY OF THE INVENTION

In the following, the elements of the invention will be described. Theseelements are listed with specific embodiments, however, it should beunderstood that they may be combined in any manner and in any number tocreate additional embodiments. The variously described examples andpreferred embodiments should not be construed to limit the presentinvention to only the explicitly described embodiments. This descriptionshould be understood to support and encompass embodiments which combinetwo or more of the explicitly described embodiments or which combine theone or more of the explicitly described embodiments with any number ofthe disclosed and/or preferred elements. Furthermore, any permutationsand combinations of all described elements in this application should beconsidered disclosed by the description of the present applicationunless the context indicates otherwise.

In a first aspect, the present invention relates to a method ofdetermining if a patient is likely to respond to a treatment with atargeted therapy compound selected from protein kinase inhibitors, smallmolecule inhibitors, and monoclonal antibody-based compounds, whereinthe method comprises the following steps:

-   i) providing a tumor sample of a patient, wherein said tumor sample    comprises cancerous tissue and/or cancerous cells,-   ii) determining a level of phosphorylated tristetraprolin (TTP) in    said tumor sample, and-   iii) comparing the level of phosphorylated TTP determined in    step ii) to a control, wherein said control is preferably a    reference value and/or a reference sample,

wherein an increased level of phosphorylated TTP in said tumor samplecompared to said control indicates that said patient is likely torespond to a treatment using a targeted therapy compound.

In one embodiment, said method further comprises

-   providing a tumor sample of said patient, and treating said tumor    sample with one or more targeted therapy compound(s),-   determining a level of phosphorylated TTP in said treated tumor    sample, and, comparing the level of phosphorylated TTP determined in    said treated tumor sample to the level of phosphorylated TTP    determined in step ii),-   wherein a decreased level of phosphorylated TTP in said treated    tumor sample compared to the level of phosphorylated TTP determined    in step ii) indicates that said patient is likely to respond to a    treatment with said one or more targeted therapy compound(s).

In one embodiment, said determining of a level of phosphorylated TTP isperformed using an antibody or antigen-binding fragment thereoftargeting phosphorylated TTP and/or TTP.

In one embodiment, said step ii) further comprises determining acancer-related genetic variation in said tumor sample, such as a KRASmutation and/or an EGFR amplification.

In a further aspect, the present invention further relates to a methodof identifying a targeted therapy compound selected from protein kinaseinhibitors, small molecule inhibitors, and monoclonal antibody-basedcompounds for personalized medicine, preferably precision cancer therapyof a cancer patient, comprising, in any order, the following steps:

-   a. obtaining a tumor sample from a patient,-   b. optionally, determining a level of phosphorylated TTP in said    tumor sample,-   c. providing one or more targeted therapy compound(s) to be tested,-   d. treating said tumor sample with said one or more targeted therapy    compound(s),-   e. determining whether said one or more targeted therapy compound(s)    reduce(s) the levels of phosphorylated TTP in said treated sample    compared to a control,

wherein a reduction in the level of phosphorylated TTP indicates thatsaid one or more targeted therapy compound(s) is/are effective fortreating said patient.

In one embodiment, said control in step e) is a level of phosphorylatedTTP determined in step b), and/or is a reference value, and/or is alevel of phosphorylated TTP determined in a reference sample.

In one embodiment, said reduction is a reduction by at least 15%,preferably by at least 20%, more preferably by at least 25%.

In one embodiment, said level of phosphorylated TTP is determined usingan antibody or antigen-binding fragment thereof targeting phosphorylatedTTP.

In one embodiment, the precision cancer therapy is a pan-cancerprecision cancer therapy capable of treating a cancer regardless of thetissue type or subtype or molecular sub-type of the cancer includingsolid tumors, hematological tumors, leukemias, lymphomas, organspecifictumors such as breast, colon, prostate, liver, and metastatic tumors ofany origin, including subtypes such as hormone positive, hormonenegative, Microsatellite Instability high or low, KRAS mutant, p53mutant cancer, and cancers with amplified genes.

In a further aspect, the present invention further relates to a methodof treatment of cancer in a patient, wherein said cancer ischaracterized by an increased level of phosphorylated TTP in cancercells compared to non-cancerous cells, wherein said method comprisesadministering an effective dose of a targeted therapy compound selectedfrom protein kinase inhibitors, small molecule inhibitors, andmonoclonal antibody-based compounds to a patient in need thereof havingsaid cancer.

In one embodiment, said method comprises the steps of:

-   a. obtaining a tumor sample, and optionally a non-tumor control    sample, from the patient,-   b. determining the level of phosphorylated TTP in said tumor sample,    and optionally in said non-tumor control sample,-   c. administering a therapeutically effective amount of said targeted    therapy compound, if there is an increased level of phosphorylated    TTP in the tumor sample compared to a control, which is optionally    the non-tumor control sample of said patient, as determined in step    b).

In one embodiment, said targeted therapy compound is selected fromBI-3406, lapitinib, AZ628, sorafenib2, TAK-6323, regorafenib4,CEP-32496, cabozantinib, and polo-like kinase inhibitors includingPCM-075, volasertib, BI 2536, rigosertib (ON 01910), HMN-214, GSK461364,R03280, NMS-P937, TAK-960, cyclapolin 1, DAP-81, ZK-thiazolidinone,compound 36 (imidazopyridine derivative), LFM-A13, poloxin (thymoquinonederivative), poloxipan, purpurogallin (benzotropolone-containingcompound), MLN0905, and SBE13, preferably volasertib and lapitinib.

In one embodiment, said targeted therapy compound is co-administeredwith a chemotherapeutic agent, and/or with a therapeutic monoclonalantibody or antigen-binding fragment thereof, and/or with a checkpointinhibitor including CTLA-4, PD-1, and PD-L1 targeting agents, and/orwith an interferon selected from Type-I IFN, Type-II IFN and Type-IIIIFN, and/or with a cytokine inhibitor, and/or with a small moleculedrug.

In one embodiment, the level of phosphorylated TTP is reduced byadministering said targeted therapy compound.

In one embodiment, said reduction is a reduction by at least 15%,preferably by at least 20%, more preferably by at least 25%.

In one embodiment, the method of treatment of cancer in a patientcomprises, prior to said administering, a method of determining if apatient is likely to respond to a treatment as defined in any of theembodiments above and/or a method of identifying a targeted therapycompound for personalized medicine as defined in any of the embodimentsabove.

In one embodiment, the method further comprises monitoring a treatmentresponse, comprising the following steps:

-   i) obtaining a sample from said patient of a first time point and a    second time point,-   ii) determining a level of phosphorylated TTP in said first sample    of said first time point and in said second sample of said second    time point,-   iii) comparing the level determined in said first sample to the    level determined in said second sample,

wherein a decrease in the level determined in the second sample comparedto the level determined in the first sample indicates that said targetedtherapy compound is effective in treating said cancer.

In a further aspect, the present invention further relates to a targetedtherapy compound selected from protein kinase inhibitors, small moleculeinhibitors, and monoclonal antibody-based compounds for use in a methodof treatment of cancer in a patient, wherein said cancer ischaracterized by an increased level of phosphorylated TTP in cancercells compared to non-cancerous cells, wherein said method comprisesadministering an effective dose of said targeted therapy compound to apatient in need thereof having said cancer.

In one embodiment, said method comprises the steps of:

-   a. obtaining a tumor sample, and optionally a non-tumor control    sample, from the patient,-   b. determining the level of phosphorylated TTP in said tumor sample,    and optionally in said non-tumor control sample,-   c. administering a therapeutically effective amount of said targeted    therapy compound, if there is an increased level of phosphorylated    TTP in the tumor sample compared to a control, which is optionally    the non-tumor control sample of said patient, as determined in step    b).

In one embodiment, said targeted therapy compound is selected fromBI-3406, lapitinib, AZ628, sorafenib2, TAK-6323, regorafenib4,CEP-32496, cabozantinib, and polo-like kinase inhibitors includingPCM-075, volasertib, BI 2536, rigosertib (ON 01910), HMN-214, GSK461364,R03280, NMS-P937, TAK-960, cyclapolin 1, DAP-81, ZK-thiazolidinone,compound 36 (imidazopyridine derivative), LFM-A13, poloxin (thymoquinonederivative), poloxipan, purpurogallin (benzotropolone-containingcompound), MLN0905, and SBE13, preferably volasertib and lapitinib.

In one embodiment, said targeted therapy compound is co-administeredwith a chemotherapeutic agent, and/or with a therapeutic monoclonalantibody or antigen-binding fragment thereof, and/or with a checkpointinhibitor including CTLA-4, PD-1, and PD-L1 targeting agents, and/orwith an interferon selected from Type-I IFN, Type-II IFN and Type-IIIIFN, and/or with a cytokine inhibitor, and/or with a small moleculedrug.

In one embodiment, in said method, the level of phosphorylated TTP isreduced by administering said targeted therapy compound.

In one embodiment, said reduction is a reduction by at least 15%,preferably by at least 20%, more preferably by at least 25%.

In a further aspect, the present invention further relates to the use ofphosphorylated TTP as a biomarker.

In a further aspect, the present invention further relates to the use ofa targeted therapy compound selected from protein kinase inhibitors,small molecule inhibitors, and monoclonal antibody-based compounds forthe manufacture of a medicament for a cancer that is characterized by anincreased level of phosphorylated TTP in cancer cells compared tonon-cancerous cells.

In this aspect, said targeted therapy compound, said cancer, and saidincreased level of phosphorylated TTP are as defined above.

BRIEF DESCRIPTION OF THE FIGURES

The present invention is now further described by reference to thefollowing figures.

All methods mentioned in the figure descriptions below were carried outas described in detail in the examples.

FIGS. 1A-1C show phosphorylated TTP status in cancer cells. 1A)Characterization of the protein bands in WB with anti-TTP/ZFP36; lysateswere treated with calf intestinal phosphatase (CIP) before separation ongels. Arrow indicates the phosphorylated form. 1B-1C) Determination ofTTP/ZFP36 and ZFP36L1 phosphorylation patterns in MDA-MB-231 and HEK293cells; the cells were transfected either with control, ZFP36-HA orZFP36L1-HA vectors; lysates were treated with CIP. Western blotting wasperformed using anti-HA as indicated. WBs are representative blot fromtwo experiments.

FIGS. 2A-2C show that kinase inhibition reduces phosphorylated TTP. 2A)Dose response for the PLK1 inhibitor (volasertib) effect onphosphorylated TTP level; WB shown is from one experiment of two. 2B-2C)Time course of volasertib (330 nM) action on phosphorylated TTP and itstarget, uPA; WBs are representative of at least two independentexperiments.

FIGS. 3A-3C show that kinase activity increases the abundance ofphosphorylated ZFP36. 3A) Ectopic expression of PLK1 in MCF10A; thecells were transfected with PLK1 vector (0.5 µg/million cells) for 24hrs. The abundance of the phosphorylated TTP/ZFP36 was evaluated by WB(one shown from two independent experiments). 3B) Co-transfection ofHEK293 with PLK1 and TTP/ZFP36; the cells were co-transfected with PLK1(0.2 µg/well) and ZFP36 (0.3 µg/million cells), then the abundance ofphosphorylated ZFP36 was assessed by WB (one shown from two independentexperiments). 3C) The effect of PLK1 overexpression in MCF10A cells onthe endogenous IL-8 mRNA and protein expression; cells transfected withPLK1 vector (3 µg/million cells) for 24 hrs, then the IL-8 mRNA wasmeasured using RT-QPCR. Data (Mean ± SEM of replicates) from oneexperiment of two.

FIGS. 4A-4B show kinase inhibition in mice and reduction in TTPphosphorylation. 4A) PLK1 inhibition and tumor size in mice; MDA-MB-231xenografts were injected into the mammary fat pad of female nude mice;when tumors become palpable, mice were treated with either volasertib(10 mg/kg) or vehicle twice weekly. The tumor size was calculated asdescribed in Methods. Data are Mean ± SEM from a nine-mouse experimentas indicated. Two-way ANOVA was performed for overall effect withSidak’s multiple comparison test (*p<0.05, ****p<0.0001). 4B) The effectof volasertib on TTP/ZFP36 phosphorylation; WB of tumor tissues fromeach mouse as probed with anti-TTP/ZFP36 or GAPDH as the loadingcontrol.

FIG. 5 shows changes in the level of phosphorylated TTP as analyzedusing Western blotting. HEK293 cells were transfected with a TTPexpression plasmid and with an expression plasmid encoding one of theshown cancer genes. The shown cancer genes are examples of genes knownto be amplified in cancer.

FIGS. 6A-6C shows a relation of ERBB2 and TTP phosphorylation. 6A) ERBB2which is known to be amplified and over-expressed in Her2 (ERBB2)positive cancer is shown to increase the phosphorylated TTP in a HEK293cell line that lacks ERBB2. 6B) The ERBB2 inhibitor, lapatinib, is shownto reduce the levels of phosphorylated TTP in the ERBB2 overexpressingbreast cancer cell line SKBR3. 6C) Normal-like MCF10A breast cells havelower levels of phosphorylated TTP than SKBR3 cells having amplified(overexpressed) ERBB2.

DETAILED DESCRIPTION

The present invention relates to a novel biomarker for use in thetreatment of cancer. In particular aspects, the invention relates to atargeted therapy approach and/or precision oncology tool based on thephosphorylation of the protein tristetraprolin (TTP/ZFP36) that plays arole in diseases such as cancer, chronic inflammatory conditions, andautoimmune diseases. TTP phosphorylation is herein shown to be aclinically useful biomarker for the diagnosis and prognosis of cancer.The analysis of TTP phosphorylation may be used as a cancer targetedtherapy tool to select kinase inhibitors for the treatment of diseasessuch as cancer, particularly by monitoring whether a kinase inhibitorreduces the level of phosphorylated TTP.

Even when a drug targets a cancer subtype with a specific mutation, thetherapy response varies among cancer patients, due to existence of othergene mutations and signaling aberrations. Thus, an additional“personalized” approach is needed for pinpointing a patient that willlikely respond to a treatment. The present inventors herein disclose thephosphorylation of tristetraprolin (TTP/ZFP36) as a biomarker, i.e. as adiagnostic and/or therapeutic tool for drugs such as BI-3406. TTP is anRNA-binding protein that promotes the decay of the hundreds AU-richmRNAs which are involved in cancer. In cancer, TTP activity isdiminished due to phosphorylation resulting in prolongation of AU-richmRNA half-life and subsequently overexpression of cancer proteins. TTPphosphorylation can occur due to multiple signaling pathways includingboth the MAPK/ERK pathway and the p38 MAPK pathway. Specifically, forexample oncogenic RAS signaling can lead to TTP phosphorylation and thusincreased abundance of mRNA and proteins encoded by cancer-relatedgenes. The present inventors demonstrate that TTP phosphorylation is ahighly useful tool for monitoring a drug response, such as a responsetowards a protein kinase inhibitor and/or RAS::SOS1 inhibitor.

The present inventors show that mice treated with an exemplary targetedtherapy compound, namely a protein kinase inhibitor which is PLK1inhibitor volasertib, reduced tumor growth. Furthermore, the presentinventors demonstrate a surprising and remarkable decrease in theabundance of phosphorylated TTP/ZFP36, both in vivo and in vitro, bymeans of a targeted therapy compound, such as a protein kinaseinhibitor. Accordingly, the present invention provides a biomarker,which is phosphorylated TTP, that can be used for analyzing whether atargeted therapy compound, such as a protein kinase inhibitor, is likelyto be effective in the treatment of a disease such as cancer.Particularly, the present invention provides a biomarker whichindicates, if levels of phosphorylated TTP are increased in a patientcompared to a control, that a targeted therapy compound, such as aprotein kinase inhibitor is likely to be effective in the treatment ofsaid patient. Furthermore, said biomarker is a tool for selecting thetargeted therapy compound from several targeted therapy compound whichis likely to be most effective in a patient, namely by analyzing theresponse of a sample of a patient to multiple targeted therapy compoundand choosing the targeted therapy compound which is most effective.Accordingly, using phosphorylated TTP as a biomarker allows forpredicting and/or determining the effectiveness of a treatment.

Thus, determining the level of phosphorylated TTP in a sample of apatient, and optionally determining the response of said sample to atargeted therapy compound as determined by the level of phosphorylatedTTP after treatment with the targeted therapy compound, allows forselecting the most successful targeted therapy compound for theparticular patient, as well as the patient’s cancer type, and is thus auseful tool for personalized medicine. In one embodiment, a targetedtherapy compound is preferably a protein kinase inhibitor.

In one embodiment, TTP phosphorylation is used as a biomarker in an invitro assay. In one embodiment, TTP phosphorylation is used as abiomarker in cancer cell lines for determining whether said cancer celllines respond to a drug that is administered to said cell lines. In oneembodiment, endogenous TTP phosphorylation is determined in KRAS-mutantcell lines. In one embodiment, the present invention relates to anantibody-based detection test for personalized medicine, in which TTPphosphorylation is analyzed prior to and after administering a drugcandidate to a patient and/or to a sample of a patient.

The term “cancer”, as used herein, refers to a disease characterized bydysregulated cell proliferation and/or growth. The term comprises benignand malignant cancerous diseases, such as tumors, and may refer to aninvasive or non-invasive cancer. The term comprises all types ofcancers, including carcinomas, sarcomas, lymphomas, germ cell tumors,and blastomas.

The term “sample”, as used herein, relates to a specimen. In oneembodiment, a patient sample is any of a solid sample, such as aformalin-fixed and/or paraffin-embedded tissue, a fresh tissue, a frozentissue, and/or a patient-derived xenograft, and a liquid sample, such asa blood sample, blood total cells, circulating tumor cells,extracellular vesicles, exosomes, lymph fluid, saliva, body fluid,and/or tissue fluid.

In one embodiment, a “tumor sample” or “sample of a cancer patient”, asused herein, relates to a sample of cancerous tissue of a patient,wherein said sample may derive from a solid or a non-solid canceroustissue. The tumor sample can be in the form of dissociated cells,aspirations, tissues, tissue slices, or any other form of obtainingtumors or tumor tissues or tumor cells known to the person skilled inthe art. A control sample or control value is used to estimate therelative phosphorylation levels of TTP in a diseased organ or tissuecompared to a healthy organ or tissue. In one embodiment, a tumor samplecomprises cancerous tissue and/or cancerous cells.

The term “cancer cell”, as used herein, refers to a cell that exhibitsabnormal proliferation and divides relentlessly, thereby forming a solidtumor or a non-solid tumor. In some embodiments of the presentinvention, cancer cell is used synonymously with “pathophysiologicalcell”.

The term “non-cancer cell”, “non-cancerous cell” or “normal cell”, asused herein, refers to a cell which is not affected by aberrantexpression, aberrant phosphorylation, and/or abnormal proliferation, anddoes not derive from cancerous tissue. In some embodiments of thepresent invention, the terms “normal cell” and “non-cancer cell” areused synonymously with “physiological cell”.

A “control”, as used herein, relates to a reference value and/or areference sample which preferably reflect the characteristics of ahealthy subject. In one embodiment, the terms “reference sample” and“control sample” are used interchangeably. A “control sample”, as usedherein, relates to a sample comprising normal cells, i.e. non-cancerouscells, for determining normal expression and/or phosphorylation levelsin non-cancerous cells. Such a control sample may derive from thepatient, wherein said control sample is taken from a healthy tissue,wherein said healthy tissue may derive from the same organ as the tumorsample of the cancerous disease, but a different site not affected bysaid cancerous disease, or may derive from a different organ notaffected by said cancerous disease. A control sample may also relate toa sample of non-cancerous tissue of a healthy individual, or to a sampleof a population of healthy individuals. In some embodiments, saidcontrol sample(s) may also relate to “control values” which reflect thenormal expression and/or phosphorylation levels obtained from analysisof expression and/or phosphorylation in control samples, wherein saidcontrol samples derive from healthy tissue of the patient, or healthytissue of a healthy individual, or healthy tissue of a population ofhealthy subjects.

The term “cancer-related genes” and “cancer-related proteins”, as usedherein, refers to genes and proteins, respectively, that are associatedwith cancerous diseases, and/or the development of cancerous diseases,and/or metastasis. In one embodiment, aberrant expression and aberrantphosphorylation of said cancer-related genes and cancer-relatedproteins, respectively, promotes formation of a cancerous disease. Inone embodiment, cancer-related genes refer to proto-oncogenes.

The term “AU-rich element” or “ARE”, as used herein, refers to anadenylate-uridylate-rich element in the 3′ untranslated region of amRNA. AREs are a determinant of RNA stability, and often occur in mRNAsof proto-oncogenes, nuclear transcription factors, and cytokines. TTP isan ARE-binding protein (ARE-BP) which binds to AREs and destabilizes themRNA. The terms “increased TTP phosphorylation”, “increasedphosphorylation”, and “increased level of phosphorylated TTP”, as usedherein, refer to an elevated phosphorylation level of TTP in a sample ofa patient as compared to the phosphorylation level of TTP in a control,referred to as “normal phosphorylation”. In some embodiments,phosphorylation is compared to normal phosphorylation in a controlsample, which may derive from healthy tissue of the same individual,wherein said healthy tissue may derive from a different site of the sameorgan as the cancerous tissue, or from a healthy individual. In someembodiments, phosphorylation is compared to normal phosphorylation in ahealthy subject population. An elevated phosphorylation level may alsobe referred to as “increased phosphorylation level”. In one embodiment,an increased phosphorylation is an at least 5 % increasedphosphorylation level, preferably at least 15 % increasedphosphorylation level in a tumor sample compared to a control. The term“decreasing phosphorylation”, as used herein, relates to decreasingelevated phosphorylation levels of TTP, to normalize said increasedphosphorylation to normal phosphorylation, preferably by administering atargeted therapy compound such as a protein kinase inhibitor. In oneembodiment, said decreasing phosphorylation is a decrease by at least 15%, preferably by at least 20 %, more preferably by at least 25 %.Methods for determining the phosphorylation level of a protein such asTTP are known to a person skilled in the art, and include western blot,ELISA, microarrays, immunohistochemistry, immunofluorescence, and massspectrometry.

The term “normal phosphorylation” or “normal phosphorylation levels”, asused herein, refers to phosphorylation levels in non-cancerous cellswhich are not affected by aberrant phosphorylation. In one embodiment,normal phosphorylation relates to phosphorylation levels of TTP innon-cancerous cells. In one embodiment, normal phosphorylation levels ofTTP are assessed in a sample of the same subject from which the tumorsample is taken. In one embodiment, normal phosphorylation levels areassessed in a sample from a healthy subject. In one embodiment, normalphosphorylation levels are assessed in a population of healthyindividuals.

The terms “normalizing” and “normalizing phosphorylation”, as usedherein, relate to normalizing or restoring phosphorylation levels of TTPto healthy, non-cancerous, normal phosphorylation levels, which can beachieved by administering an effective dose of a targeted therapycompound such as a protein kinase inhibitor to a patient in need thereofhaving abnormal phosphorylation of TTP. In one embodiment, whenreferring to “normalizing phosphorylation”, it is meant that the levelof post-transcriptional regulation of TTP phosphorylation in a cancercell adjusts to a level of post-transcriptional regulation of TTP thatis present in a non-cancerous cell, preferably by treatment with atargeted therapy compound such as a protein kinase inhibitor. In oneembodiment, a “normalizing effect” refers to an effect, preferably aneffect of a targeted therapy compound, which induces a normalization ofabnormal TTP phosphorylation levels in cancer cells towards the TTPphosphorylation levels typically found in non-cancerous cells. In oneembodiment, an “aberrant” TTP phosphorylation mean phosphorylation thatdeviate from “normal” phosphorylation in an individual not sufferingfrom cancer, respectively.

The term “TTP” or “tristetraprolin”, as used herein, refers to a proteinwhich binds to AU-rich elements (AREs) in the 3′-untranslated regions ofARE-containing mRNAs, and promotes degradation of said mRNAs. TTP isalso known as zinc finger protein 36 homolog (ZFP36). In one embodiment,interactions of TTP and target mRNAs are affected by the phosphorylationstate of TTP. In one embodiment, phosphorylated TTP/ZFP36 is unable topromote ARE-mRNA decay, and thus the abundance of proteins involved ininflammation and cancer is increased and the half-life of these proteinsis prolonged. In one embodiment, phosphorylated TTP is a biomarker fordetecting whether a patient is likely to respond to a targeted therapycompound such as a protein kinase inhibitor and/or for detecting whichtargeted therapy compound such as a protein kinase inhibitor will havethe best therapeutic effect in a patient. The term “responding to atreatment”, as used herein, relates to a therapeutic effect beingeffectively evoked in a patient. In one embodiment, phosphorylated TTPis a biomarker to be used in personalized medicine.

The term “protein kinase”, as used herein, refers to an enzyme capableof phosphorylating other proteins by transferring a phosphate group froma nucleoside triphosphate to amino acids of proteins, such as serine andthreonine, and/or tyrosine. Phosphorylation of proteins may result infunctional modification of said proteins by changing cellular location,activity, and/or associated with other proteins. In one embodiment, aprotein kinase may relate to a serine/threonine-specific protein kinaseor a tyrosine-specific protein kinase.

The term “inhibitor”, as used herein, refers to an enzyme inhibitor orreceptor inhibitor which is a molecule that binds to an enzyme orreceptor, and decreases and/or blocks its activity, for example aprotein kinase inhibitor. The term may relate to a reversible or anirreversible inhibitor. The term “small molecule inhibitor” relates to asmall molecule which inhibits a signaling pathway in a patient’s body,preferably a disease-related signaling pathway, more preferably acancer-related signaling pathway. In one embodiment, a small moleculeinhibitor is BI-3406.

The term “antigen-binding fragment thereof”, as used herein, relates toa peptide that specifically binds to an antigen. In one embodiment, anantigen-binding fragment is based on an immunoglobulin, such as apolyclonal or monoclonal antibody, for example a substantially intactantibody, a Fab fragment, a F(ab′)2 fragment, a diabody, a single chainFv fragment, a tetrabody, a triabody, a disulfide bond-stabilized Fv(dsFv), or a heavy chain VHH fragment from camels, or is based on aprotein scaffold structure having antigen-binding capacity, such as ananticalin protein, an Affilin, an Affimer, an Affitin, an Alphabody, ananobody, or a DARPin, preferably comprising antigen-bindingdeterminants, such as a CDR, of an antibody. In one embodiment, anantibody and/or antigen-binding fragment targets phosphorylated TTPand/or TTP, i.e. specifically binds to phosphorylated TTP and/or TTP.

The term “protein kinase inhibitor”, as used herein, refers to aninhibitor that blocks the action of one or more protein kinases. In oneembodiment, said term relates to an inhibitor that attenuates the actionof one or more protein kinases. In one embodiment, said protein kinaseinhibitor is a serine/threonine protein kinase inhibitor, such as aB-Raf kinase inhibitor or a polo-like kinase inhibitor, or a tyrosinekinase inhibitor, for example a VEGFR2 inhibitor. The term “PLK-1” or“polo-like kinase 1”, as used herein, refers to a specific kinase beinga member of the family of polo-like kinases. A list of examples forkinase inhibitors are given in Table 2 in Example 7. In one embodiment,a protein kinase inhibitor is preferably an inhibitor of a MAP kinase,such as an inhibitor of MK2 and/or ERK, an inhibitor of AKT, and/or aninhibitor of ERBB2, such as lapitinib. In one embodiment, phosphorylatedTTP is used as a biomarker for determining whether a patient, preferablya breast cancer patient, is likely to respond to a treatment with aninhibitor of ERBB2 phosphorylation, preferably lapitinib. In oneembodiment, a method of determining if a patient is likely to respond toa treatment and/or a method of identifying a targeted therapy compoundsuch as a protein kinase inhibitor for personalized medicine comprises apatient of breast cancer, preferably a HER+ breast cancer, and atargeted therapy compound being lapitinib. In one embodiment, the term“compound” and/or “targeted therapy compound” preferably relates to aprotein kinase inhibitor. In one embodiment, a protein kinase inhibitormay be a small molecule and/or a monoclonal antibody-based compound.

The term “administering”, as used herein, refers to applying a targetedtherapy compound, such as a protein kinase inhibitor, to a target, suchas a patient and/or a sample of a patient. In one embodiment,administering relates to in vitro and/or in vivo administration. In oneembodiment, administering relates to intravenous, oral, nasal, mucosal,intrabronchial, intrapulmonary, intradermal, subcutaneous,intramuscular, intravascular, intrathecal, intraocular, intraarticular,intranodal, intratumoral, or intrametastatical administration of atargeted therapy compound, such as a protein kinase inhibitor to apatient in need thereof. In one embodiment, administering may alsorelate to in vitro administration, namely to incubating a cell and/ortissue, e.g. a sample obtained from a patient, with a targeted therapycompound such as a protein kinase inhibitor.

The term “co-administering”, as used herein, refers to a combinedadministration of a targeted therapy compound, such as a protein kinaseinhibitor with at least one other substance, such as a chemotherapeuticagent, a checkpoint inhibitor, and/or IFN, to a target such as a patientand/or sample. In one embodiment, co-administration of a targetedtherapy compound, such as a protein kinase inhibitor with at least oneother substance allows for targeting more than one aberrant pathway.

The term “effective dose”, as used herein, refers to a dose of a drug,such as a targeted therapy compound, which is in the range between thedose sufficient to evoke a therapeutic effect and the maximum tolerateddose. In one embodiment, a method of treatment of cancer according tothe present invention comprises administering an effective dose of atargeted therapy compound, such as a protein kinase inhibitor to apatient in need thereof having an increased level of phosphorylated TTPcompared to a control. In one embodiment, said effective dose is in adose range established for a different method of treatment comprisingadministering said targeted therapy compound, such as said proteinkinase inhibitor, wherein said different method of treatment is for adisease, which is not characterized by increased TTP phosphorylationlevels in pathophysiological cells compared to physiological cells. Inone embodiment, said protein kinase inhibitor is volasertib orlapitinib, and said effective dose is in the range of 150 mg to 300 mgonce per day to once per week. In one embodiment, the terms “effectivedose” and “effective amount” are used interchangeably.

The term “treating”, as used herein, refers to applying a targetedtherapy compound, such as a protein kinase inhibitor, to a target suchas a patient and/or a sample of a patient. In one embodiment, saidtreating relates to in vivo treating of a patient, and/or to in vitrotreating of a sample of a patient. In one embodiment, in vitro treatingrelates to treating a sample with a targeted therapy compound such as aprotein kinase inhibitor for at least 15 min, preferably 4-8 h. In oneembodiment, in vitro treating relates to treating a sample with atargeted therapy compound at a concentration of from 1 nM to 10 µM.

The term “determining a level of phosphorylated TTP”, as used herein,relates assessing the level of phosphorylated TTP comprising any methodcapable of detecting a phosphorylation status of a protein that is knownto a person skilled in the art, such as methods using reactions betweenan antibody (or antigen-binding fragment) and an antigen, said antigenpreferably being phosphorylated TTP, for example western blotting,immunohistochemistry, immunofluorescence, mass spectrometry, flowcytometry, FACS, and ELISA. In one embodiment, said determiningcomprises detecting the total amount of phosphorylated TTP and/ordetecting the fraction of phosphorylated TTP compared to total TTP. Inone embodiment, an increased level of phosphorylated TTP relates to anincreased total amount of phosphorylated TTP and/or to an increasedphosphorylation degree of TTP, wherein an increased phosphorylationdegree of TTP means that the ratio of phosphorylated TTP tounphosphorylated TTP is increased. In one embodiment, the level ofphosphorylated TTP is determined using an antibody targetingphosphorylated TTP and/or is determined using an antibody targeting TTP.In one embodiment, if an antibody targeting TTP is used to determine thelevel of phosphorylated TTP, the molecular weight and/or size differencebetween a phosphorylated TTP and an unphosphorylated TTP is taken intoaccount to determine the level of phosphorylated TTP, whereinphosphorylated TTP is larger than TTP, as observed, for example, withthe bands obtained in western blotting. In one embodiment,phosphorylated TTP is detected by anti-phosphorylated TTP using westernblotting, immunohistochemistry, immunofluorescence, or any other methodcapable of detecting phosphorylated TTP known to a person skilled in theart. In one embodiment, determining a level of phosphorylated TTPrelates to assessing the protein level of phosphorylated TTP and/orunphosphorylated TTP. In one embodiment, phosphorylated TTP is used as abiomarker, and thus the level of phosphorylated TTP is determined in amethod of determining if a patient is likely to respond to a treatmentaccording to the present invention and/or a method of identifying atargeted therapy compound such as a protein kinase inhibitor forpersonalized medicine. In one embodiment, determining a level ofphosphorylated TTP comprises using phosphorylated TTP as a biomarker.

The term “patient”, as used herein, refers to a human or an animalhaving a cancer which is characterized by increased levels ofphosphorylated TTP in cancer cells compared to normal cells. The terms“subject” and “individual”, as used herein, are used synonymously, andrelate to a human or an animal.

The term “chemotherapeutic agent”, as used herein, refers to a cytotoxicagent which is of use in chemotherapy of cancer. For example, achemotherapeutic agent may relate to an alkylating agent, such ascyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine,nitrosoureas, and temozolomide, or to an anthracycline, such asdaunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone,valrubicin, or to a cytoskeletal disruptor, such as paclitaxel,docetaxel, abraxane, and taxotere, or to an epothilone, or to a histonedeacetylase inhibitor, such as vorinostat and romidepsin, or to aninhibitor of topoisomerase I, such as irinotecan and topotecan, or to aninhibitor of topoisomerase II, such as etoposide, teniposide, andtafluposide, or to a kinase inhibitor, such as bortezomib, erlotinib,gefitinib, imatinib, vemurafenib, and vismodegib, or to a nucleotideanalogue, such as azacitidine, azathioprine, capecitabine, cytarabine,doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine,methotrexate, and tioguanine, or to a peptide antibiotics, such asbleomycin and actinomycin, or to a platinum-based agent, such ascarboplatin, cisplatin, and oxaliplatin, or to a retinoid, such astretinoin, alitretinoin, and bexarotene, or to a vinca alkaloidderivative, such as vinblastine, vincristine, vindesine, andvinorelbine. In one embodiment, in a method of treatment of canceraccording to the present invention, a chemotherapeutic agent isco-administered with said targeted therapy compound such as a proteinkinase inhibitor, wherein preferably, said chemotherapeutic agent iscommonly used for the same type of cancer.

The term “checkpoint inhibitor”, as used herein, refers to an agent usedin cancer immunotherapy. A checkpoint inhibitor blocks an inhibitoryimmune checkpoint and thus restores immune system function, for example,an inhibitor of the immune checkpoint molecule CTLA-4, such asipilimumab, or an inhibitor of PD-1, such as nivolumab or pembrolizumab,or an inhibitor of PD-L1, such as atezolizumab, avelumab, anddurvalumab.

In many of the embodiments, a checkpoint inhibitor relates to anantibody which targets a molecule involved in an immune checkpoint.

The term “interferon”, or “IFN”, as used herein, refers to a group ofcytokines which are used for communication between cells and whichtrigger the immune system. Interferons comprise three classes which areType-I interferons, Type-II interferons, and Type-III interferons. Inone embodiment, said targeted therapy compound is co-administered with aType-I, Type-II or Type-III IFN. The term “Type-I IFN”, as used herein,relates to a large subgroup of interferons comprising IFN-α, IFN-β,IFN-ε, IFN-κ, IFN-τ, IFN-ζ, and IFN-ω. The term “Type-II IFN”, as usedherein, relates to IFN-γ. The term “Type-III IFN”, as used herein,relates to IFN-λ1, 2, 3, and 4.

The terms “targeted cancer therapy” and “precision cancer therapy”, asused herein, relate to the prevention or treatment of a cancer in apatient by administering an effective amount of a therapeutic agent tosaid patient. Preferably, prior to administering said therapeutic agent,it is tested whether the patient is likely to respond to saidtherapeutic agent, which is then referred to as “personalized medicine”.Said cancer therapy is “targeted” (and thus “precise”) since, prior tosaid therapy, it is determined which targeted therapy compound, forexample which protein kinase inhibitor, is able to reduce increasedlevels of phosphorylated TTP in a cancer cell and/or tumor sample ofsaid patient, and said normalization of TTP phosphorylation is anindicator that the cancer/cancer cells of said patient will respond tosaid targeted therapy compound. Accordingly, a suitable targeted therapycompound, such as a suitable protein kinase inhibitor, for treating saidpatient can be chosen using a method of determining if a patient islikely to respond to a treatment according to the present inventionand/or a method of identifying a targeted therapy compound selected fromprotein kinase inhibitors, small molecule inhibitors, and monoclonalantibody-based compounds for personalized medicine according to thepresent invention. A method of determining if a patient is likely torespond to a treatment according to the present invention and/or amethod of identifying a targeted therapy compound for personalizedmedicine according to the present invention are tools for precisiononcology allowing for determining a suitable targeted therapy compound,such as a suitable protein kinase inhibitor, for treating a cancerpatient.

The term “suitable targeted therapy compound”, as used herein, relatesto a targeted therapy compound being suitable for using said targetedtherapy compound in a method of treatment of cancer in a patient. In oneembodiment, a targeted therapy compound that is “suitable” is capable ofreducing increased levels of TTP phosphorylation in a tumor sample, forexample in a method of determining if a patient is likely to respond toa treatment according to the present invention and/or in a method ofidentifying a targeted therapy compound for personalized medicineaccording to the present invention. In one embodiment, a suitabletargeted therapy compound is a suitable protein kinase inhibitor. In oneembodiment, using phosphorylated TTP as a biomarker, for example in amethod of determining if a patient is likely to respond to a treatment,allows for identifying a targeted therapy compound, e.g. a proteinkinase inhibitor and/or small molecule, which is effective for treatinga patient, for example by treating a patient sample with said targetedtherapy compound and determining whether a therapeutic effect, e.g. adecrease in the level of phosphorylated TTP, is evoked. In oneembodiment, the therapeutic effect is a decrease/reduction in the levelof phosphorylated TTP.

In one embodiment, a method of determining if a patient is likely torespond to a treatment according to the present invention and/or amethod of identifying a targeted therapy compound for personalizedmedicine according to the present invention are advantageous in thatthese methods are independent on the tumor type or tissue type, and inthat the patient’s specific cancer can be treated with one or more ofthe kinase inhibitor drugs identified with these methods, i.e. thesuitable targeted therapy compounds can be identified prior to atreatment of a patient with a targeted therapy compound.

In one embodiment, a method of determining if a patient is likely torespond to a treatment according to the present invention and/or amethod of identifying a targeted therapy compound for personalizedmedicine according to the present invention relate to universal singleassay. The term “universal single assay”, as used herein, relates to anassay which can be ubiquitously applied in the context of variouscancerous diseases that involve increased levels of phosphorylated TTP.In one embodiment, a universal single assay is not only of use for acertain cancer type, but is useful for various types of cancerousdiseases, and is thus a “pan-cancer” precision oncology approach.

The term “cancer-related genetic variation”, as used herein, relates toa genetic variation in a DNA which is associated with a cancer, such asa mutation in an allele and/or gene, a gene amplification, a fusion ofgenes, a deletion of an allele and/or gene. In one embodiment, acancer-related genetic variation is any of a mutation in KRAS, anamplification of EGFR, an EGFR exon 19 deletion, an EGFR exon 21 L858Ralteration, an ALK fusion gene, a BRAF V600E and V600K alteration, anERBB2 copy number alteration, a HER2 gene amplification, a KRAS/NRASwild-type, and a NTRK1/2/3 fusion gene. In one embodiment, if a patientsample has a KRAS mutation in the DNA, and there is an increased levelof phosphorylated TTP in the sample, then the patient is likely tobenefit from a KRAS inhibitor. In one embodiment, if a patient samplehas an EGFR amplification in the DNA, and there is an increased level ofphosphorylated TTP in the sample, the patient is likely to benefit froman EGFR kinase inhibitor. In one embodiment, a method of the presentinvention comprises determining the level of phosphorylated TTP in apatient and/or a patient’s tumor sample, and determining whether saidpatient has a genetic variation. In one embodiment, if a patient and/ora patient’s tumor sample has/have an increased level of phosphorylatedTTP, and said patient has a genetic variation, such as a KRAS mutationand/or an EGFR amplification, said patient is likely to respond to atreatment with a targeted therapy compound, preferably a protein kinaseinhibitor. In one embodiment, if a method of determining if a patient islikely to respond to a treatment is carried out without treating a tumorsample with one or more targeted therapy compound(s), said methodpreferably further comprises determining a cancer-related geneticvariation. In one embodiment, the presence of a genetic variation, e.g.mutation, in a patient and/or a patient’s sample, in addition to anincreased level of phosphorylated TTP, is a strong indicator that atargeted therapy compound, preferably a protein kinase inhibitor, willbe effective in treating said patient. In one embodiment, a geneticvariation is a variation and/or mutation in any of the targets asspecified in Table 1 in Example 6 and/or any of the targets as specifiedin Table 2 in Example 7. In one embodiment, the presence of a geneticvariation, e.g. mutation, in a target as specified in Table 1 and/orTable 2 in a patient and/or a patient’s sample, in addition to anincreased level of phosphorylated TTP, indicates that a targeted therapycompound, such as the targeted therapy compound listed in Table 1 and/orTable 2 for the respective target, will be effective in treating saidpatient.

The term “method of determining if a patient is likely to respond to atreatment”, as used herein, relates to a method in which it isdetermined whether a patient will respond to a treatment with a targetedtherapy compound, such as a protein kinase inhibitor. In one embodiment,the method of determining further comprises taking into account whetherthe patient’s DNA has cancer-related genetic variations, such asmutations.

The term “determining a cancer-related genetic variation”, as usedherein, relates to assessing whether a patient has a genetic variationthat is typically associated with a risk of obtaining a cancer. In oneembodiment, determining a cancer-related genetic variation relates todetermining a cancer biomarker in a tumor sample of a patient other thanthe biomarker being phosphorylated TTP. In one embodiment, such agenetic variation determined is a KRAS mutation and/or an EGFRamplification. In one embodiment, the methods of the present inventioncomprise determining at least two biomarkers in a tumor sample of apatient, said two biomarkers being, firstly, phosphorylated TTP, and,secondly, a biomarker other than phosphorylated TTP, e.g. a geneticvariation. In one embodiment, said cancer-related genetic variation isdetermined using the sample in which the level of phosphorylated TTP isdetermined, or using a sample different from the sample in which thelevel of phosphorylated TTP is determined, but a sample obtained fromthe same patient. In one embodiment, a cancer-related genetic variationand the level of phosphorylated TTP are determined simultaneously,optionally in the same step, or subsequently. In one embodiment, acancer-related genetic variation is determined using genotyping and/orDNA sequencing. In one embodiment, a genetic variation is a geneticvariation in any of the targets listed in Table 1 and/or Table 2.

The term “monitoring a treatment response”, as used herein, relates toevaluating the therapeutic success of a treatment. The monitoring of thetreatment response comprises obtaining samples from a first time pointand a second time point, wherein the second time point is later in theperiod of treatment than the first time point, and comparing the levelsof phosphorylated TTP determined for the first time point and the secondtime point. If the level of phosphorylated TTP decreases during thetreatment period, i.e. from a first time point to a second time point,the treatment, i.e. the protein kinase inhibitor administered to apatient, is successful in treating said patient.

The term “targeted therapy compound”, as used herein, relates to a drugselected from protein kinase inhibitors, small molecule inhibitors, andmonoclonal antibody-based compounds, preferably a drug which is used fortargeted therapy, i.e. personalized medicine. In one embodiment, atargeted therapy compound is a protein kinase inhibitor, a smallmolecule inhibitor, and/or a monoclonal antibody-based compound. Theterm “monoclonal antibody-based compound”, as used herein, relates tomonoclonal antibodies as well as antigen-binding fragments thereof, suchas Fab fragments, F(ab)₂ fragments, scFV fragments, diabodies,triabodies, scFv-Fc fragments, monobodies, and VhH fragments. In oneembodiment, a targeted therapy compound is preferably a protein kinaseinhibitor.

In the following, reference is made to the examples, which are given toillustrate, not to limit the present invention.

EXAMPLES Example 1: Materials and Methods Cell Lines

Breast cancer cell lines MDA-MB-231, the normal-like breast cell lineMCF10A, and the HEK293 kidney cell line were obtained from American TypeCulture Collection (ATCC, Rockville, MD, USA). MDA-MB-231 and HEK293cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM;Invitrogen, Carlsbad, CA, USA) at 37° C. supplemented with 2 mMglutamine and 10% fetal bovine serum (FBS). MCF10A cells were maintainedin Ham’s F12-DMEM mixture (Thermo Fisher Scientific, Waltham, MA, USA)and supplemented with 20 ng/ml epidermal growth factor (EGF), 0.01 mg/mlbovine insulin and 500 ng/ml hydrocortisone (Sigma, St. Louis, MO, USA).All culture media were supplemented with 1% penicillin-streptomycinantibiotics (Sigma-Aldrich).

Plasmids and Transfections

PLK1expression vector was obtained from Genecopoeia (Rockville,Maryland, US); vector expressing human hemagglutinin (HA)-tagged ZFP36(TTP) was described previously, and HA-tagged ZFPL36L1 (BRF1) was clonedby PCR from cDNA in a CMV-driven expression vector.

Quantitative Reverse Transcription-Polymerase Chain Reaction and mRNAHalf-Life

Total RNA was extracted using Trizol reagent (TRI Reagent,Sigma-Aldrich). The cells were lysed directly on the culture dish byadding 1 ml of the TRI Reagent per 10 cm² surface area. Reversetranscription for preparation of cDNA was performed using 3 µg of totalRNA, 150 ng random primers, 0.1 M dithiothreitol (DTT), 10 mMdeoxynucleotide triphosphate (dNTP) and 200 U of SuperScript II(Invitrogen, Foster City, CA). The quantitative RT-QPCR was performed inmultiplex in the Chroma 4 DNA Engine cycler (BioRad, Hercules, CA, USA)using FAM-labelled TaqMan probes (Applied Biosystems, Foster City, CA,USA) for IL-8 while a VIC-labelled glyceraldehyde-3-phosphatedehydrogenase (GAPDH) probe was used as the endogenous control. Sampleswere amplified in triplicate, and quantification of relative expressionwas performed using the estimation of quantitation cycle (Cq) method.

Western Blotting and TTP Phosphorylation

The cells were lysed in a mixture of 0.5% NP40 buffer, proteaseinhibitor and phosphatase inhibitor. The calf intestinal alkalinephosphatase (CIP, Promega, Madison, WI, USA) was used to verify thephosphorylation status of TTP/ZFP36, 20 units were added to the celllysate (per 250 ul). The cell lysates were loaded and subjected toelectrophoresis on 4-12% NuPAGE Bis-Tris gel (Invitrogen, Foster City,CA, USA). Then, the proteins were transferred from the gel tonitrocellulose membranes (Hybond ECL; Amersham Biosciences, Piscataway,NJ) in the presence of NuGAGE 20 x transfer buffer (Invitrogen, FosterCity, CA, USA). After blocking, membranes were incubated with primaryantibodies diluted in 5% bovine serum albumin (BSA) (Sigma-Aldrich, StLouis, MO) at 4° C. overnight. For TTP/ZFP36, a custom-made affinitypurified TTP polyclonal antibody and against C-terminal end of TTP andwas used previously [5]. This antibody is specific to TTP/ZFP36, but notthe ortholog ZFP36L1 when using 0.5% NP40 buffer instead of Laemmlibuffer. Other antibodies are: anti-PLK1 (dilution 1:1000, Cellsignaling, Massachusetts, USA), anti-GAPDH (dilution 1:500, Abcam, MA,USA), anti-HA, dilution 1:5000, Roche, Upper Bavaria, Germany).Thereafter, the membranes were incubated with corresponding secondaryantibodies (diluted in 5% BSA, 1:2000 dilution) (Santa Cruz Biotech,Santa Cruz, CA) for 1-3 hrs. Protein bands were detected using ECLWestern blotting detection reagents (Amersham Biosciences, Amersham, UK)in Molecular Imager ChemiDoc machine (BioRad, Hercules, CA, USA).

Animal Studies

Nude mice were purchased from Jackson Laboratories (Bar Harbor, Maine,USA). The mice were housed at the animal facility at King FaisalSpecialist Hospital and Research Center (KFSHRC) and maintained inaccordance with protocols approved by the institution Animal Care andUse Committee. One million MDA-MB-231 cells were suspended in 100 µl ofPBS: Matrigel (1:1 ratio), then injected into the 4th mammary fat pad offemale mice (8 weeks old) after they were anesthetized with Isoflurane.Tumors were allowed to grow for 1 week before treatment with volasertib(10 mg/kg) or DMSO alone (n= 5 mice per group). Treatment wasadministered via intraperitoneal route twice a week for four weeks afterwhich mice were sacrificed and tumors collected for RNA and proteinanalyses. Tumor growth was measured by caliper, and the volume wascalculated by the formula (π/6 × L × M2), where L and M refer to thelarge and small diameters of each tumor, respectively. Mice weight andtumor size were recorded weekly.

Statistical Analysis

Data are presented as Means ± standard error of the mean (SEM).Two-tailed student’s t-test was used when comparing two columns of data.Two-way analysis of variance was used to analyze two groups of data,each having two data columns. The analyses were performed using GraphPadPrism.

Example 2: ZFP36 Phosphorylation in Cancer Cells

TTP is an ARE-binding and mRNA decay-promoting protein that is inhibitedby phosphorylation. The present inventors analysed the effect of PLK1pharmacological targeting on TTP phosphorylation. First, by usingsensitive and specific Western blotting for both unphosphorylated andphosphorylated TTP, the present inventors observed that in thetriple-negative MDA-MB-231 cell line, TTP largely existed as a highmolecular weight species. Treatment with CIP reduced its size,indicating the phosphorylation status (FIG. 1A). Ectopicallyover-expressed TTP became phosphorylated in MDA-MB-231 and HEK293 cells,since treatment with CIP reduces its size (FIG. 1B). While the CIPtreatment of cells transfected with ZFP36L1 (BRF1), ZFP36L1 being aprotein different from ZFP36 but belonging to the same family as ZFP36,did not lead to a similar effect (FIGS. 1B and C). Both proteins aretagged with HA, allowing probing of both with antibody to HA.

When detecting by Western blotting, sizes of larger than the expectedsize (~40 kDa) indicate phosphorylated forms. Alternatively, Westernblotting can be performed in two steps, immunoprecipitation by anti-TTP,followed by immunoblot with anti-phosphoserine. Any phosphorylated siteantibody can be used since TTP has numerous potential phosphorylatedsites. There are many serine and threonine conserved sites (estimatedmore than 30) in TTP protein that be potentially phosphorylated.Currently, there are no commercially available anti-phosphorylated TTP,but, can be developed to any phosphorylatable sites in TTP protein. Thiswould facilitate immunohistochemistry or immunofluorescence particularlyon patient’s issues. Examples of amino acids that are predicted to bephosphorylated in the sequence of TTP (SEQ ID NO. 1) include but are notlimited to serine residues numbers 9, 12, 14, 21, 28, 29, 34, 35, 39,41, 43, 45, 46, 48, 42, 52, 58, 60, 66, 88, 90, 93, 98, 99, 102, 113,115, 160, 169, 184, 186, 188, 192, 197, 207, 209, 113, 210, 211, 212,216, 214, 217, 218, 228, 230, 233, 252, 260, 273, 276, 279, 286, 287,289, 290, 294, 296, 323, and 325, threonine residues numbers 4, 26, 59,92, 95, 97, 99, 100, 106, 111, 196, 238, 246, 257, and 271, and tyrosineresidues numbers 120, 151, 158, and 284.

Example 3: Kinase Inhibitor Reducing the Phosphorylation of TTP

An exemplary kinase inhibitor, namely volasertib, was tested for theeffects on the level of phosphorylation of TTP. Volasertib reduced in adose-dependent manner the abundance of total TTP and phosphorylated TTP.The maximum dosage tested was 300 nM, and the lowest tested dose was 10nM and was still effective (FIG. 2A). The time course showed that theeffect was observed as early as 2 hrs after treatment and maximal at 8hrs after treatment (FIG. 2B). There was no change in the mobility ofZFP36 as observed with CIP treatment, indicating a partial, rather thancomplete de-phosphorylation event (as with CIP). The abundance of theuPA protein was also reduced by volasertib (FIG. 2C).

Table 2 shows a list of other kinase inhibitors useful in reducing thelevel of phosphorylated TTP.

Example 4: Kinase Activity Increases the Abundance of PhosphorylatedZFP36

The effects of kinase activity on TTP phosphorylation in cancer werefurther analyzed with regard to polo like kinase 1 (PLK1). PLK1 wasover-expressed in MCF10A normal-like cells, which express low PLK1levels compared to tumor cells. PLK1 caused an increased abundance ofthe phosphorylated TTP/ZFP36 (FIG. 3A). Moreover, using HEK293 cellline, which has non-detectable amounts of PLK1 and TTP/ZFP36 proteins,the present inventors showed that co-expression of PLK1 and TTP/ZFP36led to increased abundance of the phosphorylated ZFP36 protein (FIG.3B). It was observed that PLK1 also increased in the presence of thephosphorylated TTP/ZFP36. Co-transfection with SGFP did not affect thefluorescence levels due to PLK1 indicating the increase in the ZFP36phosphorylation is not due to changes in transfection efficiency (datanot shown). PLK1 expression in MCF10A caused an increase in theabundance of IL-8 mRNA, which is TTP target (FIG. 3C) and also insecreted levels as measured by ELISA (FIG. 3D).

Example 5: The Effect of Kinase Inhibition on TTP/ZFP36 Phosphorylationin the Tumor Xenografts in Nude Mice

To study the effect of kinase inhibition on TTP phosphorylation in vivoand the subsequent effect on tumor growth, MDA-MB-231 xenografts wereinjected into the mammary fat pad of female nude mice. The kinaseinhibitor volasertib (10 mg/kg) or vehicle was administered biweeklyupon the formation of palpable tumors. While the tumors in the controlgroup continued to grow, those in the treatment group demonstrated aslower growth rate and began to regress by the end of the experiment(FIG. 4A, upper panel). A statistically significant difference in tumorvolume could be seen after 4 weeks of treatment (FIG. 4A, lower panel).These results clearly demonstrate the role of PLK1 inhibition on tumorprogression of MDA-MB-231 breast cancer cells. Next, the presentinventors examined the in vivo effect of volasertib on phosphorylatedTTP protein abundance in the excised tumor tissues. The amounts of thephosphorylated TTP/ZFP36 levels in the mice tissues were markedlyreduced due to the in vivo volasertib treatment (FIG. 4B, lanes 6-9)compared with the control (lanes, 1-5), which clearly substantiates thein vitro data.

Example 6: Exemplary Targeted Therapy Compounds and CorrespondingTargets/Indications

The list in Table 1 below shows examples of targeted therapy compoundswhich can be tested in a method of determining if a patient is likely torespond to a treatment according to the present invention, and/or in amethod of identifying a targeted therapy compound for personalizedmedicine according to the present invention. Furthermore, the examplesof targeted therapy compounds in Table 1 are exemplary targeted therapycompounds that can be used in a method of treatment of cancer in apatient.

TABLE 1 Examples of targeted therapy compounds, their targets, andFDA-approved indications. Agent Target(s) FDA-approved indication(s)Monoclonal antibodies bevacizumab humanized monoclonal antibody wit h acirculatory system target (VEGF-A) cetuximab chimeric monoclonalantibody wit h a tumor target (EGFR) ipilimumab fully human antibodywith an immune system target (CTLA-4) Small molecules bortezomib smallmolecule proteasome inhibitor imatinib small molecule tyrosine kinaseinhibitor seliciclib small molecule cyclin-dependent kinase inhibitorAdo-trastuzumab emtansine (Kadcyla) HER₂ (ERBB₂/neu) Breast cancer(HER₂+) Afatinib (Gilotrif) EGFR (HER₁/ERBB₁), HER₂ (ERBB₂/neu)Non-small cell lung cancer (with EGFR exon 19 deletions or exon 21substitution (L858R) mutations) Aldesleukin (Proleukin) Renal cellcarcinoma Melanoma Alectinib (Alecensa) ALK Non-small cell lung cancer(with ALK fusion) Alemtuzumab (Campath) CD₅₂ B-cell chronic lymphocyticleukemia Atezolizumab (Tecentriq) PD-L₁ Urothelial carcinoma Non-smallcell lung cancer Avelumab (Bavencio) PD-L₁ Merkel cell carcinomaUrothelial cancer Axitinib (Inlyta) KIT, PDGFRβ, VEGFR_(1/2/3) Renalcell carcinoma Belimumab (Benlysta) BAFF Lupus erythematosus Belinostat(Beleodaq) HDAC Peripheral T-cell lymphoma Bevacizumab (Avastin) VEGFligand Cervical cancer Colorectal cancer Fallopian tube cancerGlioblastoma Non-small cell lung cancer Ovarian cancer Peritoneal cancerRenal cell carcinoma Blinatumomab (Blincyto) CD₁₉/CD₃ Acutelymphoblastic leukemia (precursor B-cell) Bortezomib (Velcade)Proteasome Multiple myeloma Mantle cell lymphoma Bosutinib (Bosulif) ABLChronic myelogenous leukemia (Philadelphia chromosome positive)Brentuximab vedotin (Adcetris) CD₃₀ Hodgkin lymphoma Anaplastic largecell lymphoma Brigatinib (Alunbrig) ALK Non-small cell lung cancer(ALK+) Cabozantinib (Cabometyx [tablet], Cometriq [capsule]) FLT₃, KIT,MET, RET, VEGFR₂ Medullary thyroid cancer Renal cell carcinomaCanakinumab (Ilaris) IL-₁β Juvenile idiopathic arthritisCryopyrin-associated periodic syndromes Carfilzomib (Kyprolis)Proteasome Multiple myeloma Ceritinib (Zykadia) ALK Non-small cell lungcancer (with ALK fusion) Cetuximab (Erbitux) EGFR (HER₁/ERBB₁)Colorectal cancer (KRAS wild type) Squamous cell cancer of the head andneck Cobimetinib (Cotellic) MEK Melanoma (with BRAF V600E or V600Kmutation) Crizotinib (Xalkori) ALK, MET, ROS₁ Non-small cell lung cancer(with ALK fusion or ROS₁ gene alteration) Dabrafenib (Tafinlar) BRAFMelanoma (with BRAF V600 mutation) Non-small cell lung cancer (with BRAFV600E mutation) Daratumumab (Darzalex) CD₃₈ Multiple myeloma Dasatinib(Sprycel) ABL Chronic myelogenous leukemia (Philadelphia chromosomepositive) Acute lymphoblastic leukemia (Philadelphia chromosomepositive) Denosumab (Xgeva) RANKL Giant cell tumor of the boneDinutuximab (Unituxin) B₄GALNT₁ (GD₂) Pediatric neuroblastoma Durvalumab(Imfinzi) PD-L₁ Urothelial carcinoma Non-small cell lung cancerElotuzumab (Empliciti) SLAMF7 (CS₁/CD₃₁₉/CRACC) Multiple myelomaEnasidenib (Idhifa) IDH₂ Acute myeloid leukemia (with IDH2 mutation)Erlotinib (Tarceva) EGFR (HER₁/ERBB₁) Non-small cell lung cancer (withEGFR exon 19 deletions or exon 21 substitution (L858R) mutations)Pancreatic cancer Everolimus (Afinitor) mTOR Pancreatic,gastrointestinal, or lung origin neuroendocrine tumor Renal cellcarcinoma Nonresectable subependymal giant cell astrocytoma associatedwith tuberous sclerosis Breast cancer (HR+, HER2-) Gefitinib (Iressa)EGFR (HER₁/ERBB₁) Non-small cell lung cancer (with EGFR exon 19deletions or exon 21 substitution (L858R) mutations) Ibritumomabtiuxetan (Zevalin) CD₂₀ Non-Hodgkin’s lymphoma Ibrutinib (Imbruvica) BTKMantle cell lymphoma Chronic lymphocytic leukemia Waldenstrom’smacroglobulinemia Idelalisib (Zydelig) PI₃Kδ Chronic lymphocyticleukemia Follicular B-cell non-Hodgkin lymphoma Small lymphocyticlymphoma Imatinib (Gleevec) KIT, PDGFR, ABL GI stromal tumor (KIT+)Dermatofibrosarcoma protuberans Multiple hematologic malignanciesincluding Philadelphia chromosome-positive ALL and CML Ipilimumab(Yervoy) CTLA-₄ Melanoma Renal cell carcinoma Ixazomib (Ninlaro)Proteasome Multiple Myeloma Lapatinib (Tykerb) HER₂ (ERBB₂/neu), EGFR(HER₁/ERBB₁) Breast cancer (HER₂+) Lenvatinib (Lenvima) VEGFR₂ Renalcell carcinoma Thyroid cancer Midostaurin (Rydapt) FLT₃ acute myeloidleukemia (FLT₃+) Necitumumab (Portrazza) EGFR (HER₁/ERBB₁) Squamousnon-small cell lung cancer Neratinib (Nerlynx) HER₂ (ERBB₂/neu) Breastcancer (HER₂ overexpressed/amplified) Nilotinib (Tasigna) ABL Chronicmyelogenous leukemia (Philadelphia chromosome positive) Niraparib(Zejula) PARP Ovarian cancer Fallopian tube cancer Peritoneal cancerNivolumab (Opdivo) PD-₁ Colorectal cancer (dMMR and MSI-H) Head and necksquamous cell carcinoma Hepatocellular carcinoma Hodgkin lymphomaMelanoma Non-small cell lung cancer Renal cell carcinoma Urothelialcarcinoma Obinutuzumab (Gazyva) CD₂₀ Chronic lymphocytic leukemiaFollicular lymphoma Ofatumumab (Arzerra, HuMax-CD20) CD₂₀ Chroniclymphocytic leukemia Olaparib (Lynparza) PARP Ovarian cancer (with BRCAmutation) Olaratumab (Lartruvo) PDGFRα Soft tissue sarcoma Osimertinib(Tagrisso) EGFR Non-small cell lung cancer (with EGFR T₇₉₀M mutation)Palbociclib (Ibrance) CDK₄, CDK₆ Breast cancer (HR+, HER₂₋) PanitumumabEGFR (HER₁/ERBB₁) Colorectal cancer (KRAS wild type) (Vectibix)Panobinostat (Farydak) HDAC Multiple myeloma Pazopanib (Votrient) VEGFR,PDGFR, KIT Renal cell carcinoma Pembrolizumab (Keytruda) PD-₁ ClassicalHodgkin lymphoma Colorectal cancer (MSI-H/dMMR) Gastric cancer MelanomaNon-small cell lung cancer (PD-L₁+) Head and neck squamous cellcarcinoma Urothelial cancer Solid tumors (MSI-H/dMMR) Pertuzumab(Perjeta) HER₂ (ERBB₂/neu) Breast cancer (HER₂+) Ponatinib (Iclusig)ABL, FGFR₁₋₃, FLT₃, VEGFR2 Chronic myelogenous leukemia Acutelymphoblastic leukemia (Philadelphia chromosome positive) Ramucirumab(Cyramza) VEGFR₂ Colorectal cancer Gastric cancer or Gastroesophagealjunction (GEJ) adenocarcinoma Non-small cell lung cancer Regorafenib(Stivarga) KIT, PDGFRβ, RAF, RET, VEGFR₁/₂/₃ Colorectal cancerGastrointestinal stromal tumors Hepatocellular carcinoma Ribociclib(Kisqali) CDK₄, CDK6 Breast cancer (HR+, HER₂-) Rituximab (Rituxan,Mabthera) CD₂₀ Non-Hodgkin’s lymphoma Chronic lymphocytic leukemiaRheumatoid arthritis Granulomatosis with polyangiitisRituximab/hyaluronida se human (Rituxan Hycela) CD₂₀ Chronic lymphocyticleukemia Diffuse large B-cell lymphoma Follicular lymphoma Romidepsin(Istodax) HDAC Cutaneous T-cell lymphoma Peripheral T-cell lymphomaRucaparib (Rubraca) PARP Ovarian cancer (with BRCA mutation) Ruxolitinib(Jakafi) JAK₁/₂ Myelofibrosis Siltuximab (Sylvant) IL-6 MulticentricCastleman’s disease Sipuleucel-T (Provenge) Prostate cancer Sonidegib(Odomzo) Smoothened Basal cell carcinoma Sorafenib (Nexavar) VEGFR,PDGFR, KIT, RAF Hepatocellular carcinoma Renal cell carcinoma Thyroidcarcinoma Temsirolimus (Torisel) mTOR Renal cell carcinoma Tocilizumab(Actemra) IL-6R Rheumatoid arthritis Juvenile idiopathic arthritisTofacitinib (Xeljanz) JAK₃ Rheumatoid arthritis Tositumomab (Bexxar)CD₂₀ Non-Hodgkin’s lymphoma Trametinib (Mekinist) MEK Melanoma (withBRAF V6₀₀ mutation) Non-small cell lung cancer (with BRAF V6₀₀Emutation) Trastuzumab (Herceptin) HER₂ (ERBB₂/neu) Breast cancer (HER₂+)Gastric cancer (HER₂+) Vandetanib (Caprelsa) EGFR (HER₁/ERBB₁), RET,VEGFR₂ Medullary thyroid cancer Vemurafenib (Zelboraf) BRAF Melanoma(with BRAF V6₀₀ mutation) Venetoclax (Venclexta) BCL₂ Chroniclymphocytic leukemia (with ₁₇p deletion) Vismodegib (Erivedge) PTCH,Smoothened Basal cell carcinoma Vorinostat (Zolinza) HDAC CutaneousT-cell lymphoma Ziv-aflibercept (Zaltrap) PIGF, VEGFA/B Colorectalcancer

Example 7: Exemplary Protein Kinase Inhibitors

The list in Table 2 below shows examples of protein kinase inhibitorswhich can be tested in a method of determining if a patient is likely torespond to a treatment according to the present invention and/or amethod of identifying a targeted therapy compound for personalizedmedicine according to the present invention. Furthermore, the examplesof protein kinase inhibitors in Table 2 are exemplary inhibitors thatcan be used in a method of treatment of cancer in a patient.

TABLE 2 Examples of kinase inhibitors and their targets. Kinaseinhibitor Target (-)-BAY-₁₂₅₁₁₅₂ CDK (-)-Indolactam V PKC(+)-BAY-₁₂₅₁₁₅₂ CDK (±)-Zanubrutinib Btk (₁S,₃R,₅R)-PIM₄₄₇(dihydrochloride) Pim (₃S,₄S)-Tofacitinib JAK (E)-AG99 EGFR(E)-Necrosulfonamide Mixed Lineage Kinase [6]-Gingerol AMPK; Apoptosis1,2,3,4,5,6-Hexabromocyclohexane JAK 1,3-Dicaffeoylquinic acid Akt; PI3K1-Azakenpaullone GSK-3 1-Naphthyl PP1 Src 1-NM-PP1 PKD2,5-Dihydroxybenzoic acid Endogenous Metabolite; FGFR c-RET,SUMO,TAMReceptor,IL Receptor,PI3K,VEGFR,GSK-3 2-Do8 2-Deoxy-D-glucose Hexokinase2-Methoxy-1,4-naphthoquinone PKC 2-Phospho-L-ascorbic acid trisodiumc-Met/HGFR salt 3,4-Dimethoxycinnamic acid ROS 3BDO Autophagy; mTOR3-Bromopyruvic acid Hexokinase 3-Methyladenine (3-MA) Autophagy,PI3K4µ8C IRE1 5-Aminosalicylic Acid NF-kB; PAK; PPAR 5-Bromoindole GSK-35-Iodotubercidin Adenosine Kinase 6-(Dimethylamino)purineSerine/threonin kina 6-Bromo-2-hydroxy-3- IRE1 methoxybenzaldehyde7,8-Dihydroxyflavone Trk Receptor 7-Hydroxy-4-chromone Src7-Methoxyisoflavone AMPK 8-Bromo-cAMP sodium salt PKA A 419259(trihydrochloride) Src A 77-01 TGF-β Receptor A 83-01 sodium salt TGF-βReceptor A-443654 Akt A-484954 CaMK A66 PI3K A-674563 Akt,CDK,PKAA-769662 AMPK ABBV-744 Epigenetic Reader Do Abemaciclib CDK AbrocitinibJAK ABT-702 dihydrochloride Adenosine Kinase AC480 (BMS-599626)EGFR,HER2 AC710 c-Kit; FLT3; PDGFR Acalabrutinib (ACP-196) BTK AcalisibPI3K acalisib (GS-9820) PI3K ACHP (Hydrochloride) IKK ACTB-1003 FGFR;VEGFR Acumapimod p38 MAPK AD80 c-RET,Src,S6 Kinase Adavosertib Wee1AEE788 EGFR Afatinib Autophagy; EGFR Afatinib (BIBW2992) EGFR,HER2Afatinib (dimaleate) Autophagy; EGFR Afuresertib Akt AG 555 EGFR AG-1024IGF-1R AG126 ERK AG-1478 EGFR AG-18 EGFR AG-490 Autophagy; EGFR; STATAgerafenib Raf AGL-2263 Insulin Receptor AICAR AMPK; Autophagy;Mitophagy AIM-100 Ack1 AKT inhibitor VIII Akt AKT Kinase Inhibitor AktAkt1 and Akt2-IN-1 Akt Akti-½ Akt Alectinib ALK Alisertib (MLN8237)Aurora Kinase ALK inhibitor 1 ALK ALK inhibitor 2 ALK ALK-IN-1 ALKAllitinib tosylate EGFR Alofanib FGFR Alpelisib PI3K Altiratinibc-Met/HGFR; FLT3; Trk Receptor; VEGFR ALW-II-41-27 Ephrin ReceptorAM-2394 Glucokinase Amcasertib (BBI503) Stemness kinase AMG 337 c-MetAMG 900 Aurora Kinase AMG 925 (HCl) CDK; FLT3 AMG-208 c-Met/HGFR AMG319PI3K AMG-337 c-Met/HGFR AMG-3969 Glucokinase AMG-458 c-Met AMG-47a SrcAMG-900 Aurora Kinase Amlexanox Immunology & Inflammation relatedAmuvatinib (MP-470) c-Kit,FLT3,PDGFR ANA-12 Trk Receptor Anacardic AcidHistone Acetyltransferase Anlotinib (AL3818) dihydrochloride VEGFRAP26113-analog (ALK-IN-1) ALK,EGFR Apatinib VEGFR,c-RETApatinib?mesylate VEGFR Apigenin P450 (e.g. CYP17) Apitolisib mTOR; PI3KAPS-2-79 MEK APY0201 Interleukin Related; PIKfyve APY29 IRE1 AR-A014418GSK-3 ARN-3236 Salt-inducible Kinase (SIK) ARQ 531 Btk AS-252424 PI3KAS601245 JNK AS-604850 PI3K AS-605240 Autophagy; PI3K Asciminib Bcr-AblAsciminib (ABL001) Bcr-Abl ASP3026 ALK ASP5878 FGFR AST 487 Ber-Abl;c-Kit; FLT3; VEGFR AST-1306 EGFR Astragaloside IV ERK; JNK; MMP AT13148Akt,S6 Kinase,ROCK,PKA AT7519 CDK AT7867 Akt,S6 Kinase AT9283 AuroraKinase,Bcr-Abl,JAK Atuveciclib CDK Atuveciclib S-Enantiomer CDK Aurora Ainhibitor I Aurora Kinase Autophinib Autophagy,PI3 AUZ 454 CDK AV-412EGFR Avapritinib c-Kit Avitinib (maleate) EGFR AX-15836 ERK Axitinibc-Kit,PDGFR,VEGFR AZ 3146 Kinesin AZ 628 Raf AZ 960 JAK AZ1495 IRAKAZ191 DYRK AZ20 ATM/ATR AZ-23 Trk Receptor AZ304 Raf AZ31 ATM/ATR AZ3146Mps1 AZ32 ATM/ATR AZ5104 EGFR AZ960 JAK Azaindole 1 ROCK AZD 6482Autophagy; PI3K AZD0156 ATM/ATR AZD-0364 ERK AZD1080 GSK-3 AZD1152Aurora Kinase AZD1208 Pim AZD1390 ATM/ATR AZD-1480 JAK AZD2858 GSK-3AZD2932 PDGFR,VEGFR,FLT3,c-Kit AZD3229 c-Kit AZD3264 IκB/IKK AZD3463ALK,IGF-1R AZD-3463 ALK; Autophagy; IGF-1R AZD3759 EGFR AZD4547 FGFRAZD4573 CDK AZD5363 Akt AZD5438 CDK AZD-5438 CDK AZD6482 PI3K AZD6738ATM/ATR AZD7507 c-Fms AZD7545 PDHK AZD7762 Chk AZD-7762 CheckpointKinase (Chk) AZD8055 mTOR AZD-8055 Autophagy; mTOR AZD8186 PI3K AZD8330MEK AZD8835 PI3K AZD-8835 PI3K AZM475271 Src Bafetinib (INNO-406)Bcr-Abl Bakuchiol Immunology & Inflammation related Barasertib-HQPAAurora Kinase Bardoxolone Methyl IκB/IKK Baricitinib JAK BAW2881(NVP-BAW2881) VEGFR,Raf,c-RET BAY 11-7082 E2 conjugating,IκB/IKK Bay11-7085 IκB/IKK BAY 1217389 Kinesin,Serine/threonin kinase BAY 1895344(BAY-1895344) ATM/ATR Bay 65-1942 (hydrochloride) IKK BAY1125976 AktBAY1217389 Mps1 BAY-1895344 (hydrochloride) ATM/ATR BAY-61-3606 SykBDP5290 ROCK BEBT-908 PI3K Belizatinib ALK; Trk Receptor Bemcentinib TAMReceptor Bentamapimod JNK Berbamine (dihydrochloride) Bcr-Abl Berberine(chloride hydrate) Autophagy; Bacterial; ROS; Topoisomerase BerzosertibATM/ATR BF738735 PI4K BFH772 VEGFR BGG463 CDK BGT226 (NVP-BGT226)mTOR,PI3K BI 2536 PLK BI-4464 FAK; Ligand for Target Protein BI605906IKK BI-78D3 JNK BI-847325 MEK,Aurora Kinase BIBF 1202 VEGFR BIBF0775TGF-β Receptor BI-D1870 S6 Kinase Bikinin GSK-3 Bimiralisib mTOR; PI3KBinimetinib Autophagy; MEK Binimetinib (MEK162, ARRY-162, MEKARRY-438162) BIO GSK-3 BIO-acetoxime GSK-3 Biochanin A FAAHBisindolylmaleimide I PKC Bisindolylmaleimide I (GF109203X) PKCBisindolylmaleimide IX (Ro 31-8220 PKC Mesylate) BIX 02188 MEK BIX 02189MEK BIX02188 ERK; MEK BIX02189 ERK; MEK BLU-554 (BLU554) FGFR BLU9931FGFR BLZ945 CSF-1R BMS 777607 c-Met/HGFR; TAM Receptor BMS-265246 CDKBMS-345541 IκB/IKK BMS-5 LIM Kinase (LIMK) BMS-509744 Itk BMS-536924IGF-1R BMS-582949 p38 MAPK BMS-690514 EGFR; VEGFR BMS-754807c-Met,IGF-1R,Trk receptor BMS-777607 TAM Receptor,c-Met BMS-794833c-Met,VEGFR BMS-911543 JAK BMS-935177 BTK,Trk receptor,c-RET BMS-986142Btk BMS-986195 Btk BMX-IN-1 BMX Kinase; Btk BOS-172722 Mps1 Bosutinib(SKI-606) Src BPR1J-097 Hydrochloride FLT3 bpV (HOpic) PTEN BQR-695 PI4KB-Raf IN 1 Raf BRAF inhibitor Raf B-Raf inhibitor 1 Raf BrivanibAutophagy; VEGFR Brivanib (BMS-540215) FGFR,VEGFR Brivanib Alaninate(BMS-582664) FGFR,VEGFR BS-181 CDK BTK IN-1 Btk Btk inhibitor 1 Btk BTKinhibitor 1 (Compound 27) BTK Btk inhibitor 1 (R enantiomer) Btk Btkinhibitor 2 Btk Bucladesine (calcium salt) PKA Bucladesine (sodium salt)PKA Buparlisib PI3K Butein EGFR BX517 PDK-1 BX795 PDK-1 BX-795IκB/IKK,PDK BX-912 PDK Ca2+ channel agonist 1 Calcium Channel; CDKCA-4948 TLR,IL Receptor Cabozantinib c-Kit; c-Met/HGFR; FLT3; TAMReceptor; VEGFR Cabozantinib (S-malate) VEGFR Cabozantinib (XL184,BMS-907351) c-Met,VEGFR Cabozantinib malate (XL184) TAM Receptor,VEGFRCAL-130 (Hydrochloride) PI3K CaMKII-IN-1 CaMK Canertinib (CI-1033)EGFR,HER2 Capivasertib Akt; Autophagy Capmatinib c-Met/HGFR CaseinKinase II Inhibitor IV Casein Kinase CAY10505 PI3K CC-115 DNA-PK,mTORCC-223 mTOR CC-401 (hydrochloride) JNK CC-671 CDK CC-90003 ERK CCG215022PKA CCT 137690 Aurora Kinase CCT020312 Eukaryotic Initiation Factor(eIF); PERK CCT128930 Akt CCT129202 Aurora Kinase CCT137690 AuroraKinase CCT196969 Raf,Src CCT241533 (hydrochloride) Checkpoint Kinase(Chk) CCT241736 Aurora Kinase; FLT3 CCT245737 Chk CCT-251921 CDKCDK9-IN-1 CDK; HIV CDK9-IN-2 CDK CDKI-73 CDK CDK-IN-2 CDK CediranibAutophagy; PDGFR; VEGFR Cediranib Maleate VEGFR Centrinone Polo-likeKinase (PLK) Centrinone-B Polo-like Kinase (PLK) CEP-28122 (mesylatesalt) ALK CEP-32496 CSF-1R,Raf CEP-33779 JAK CEP-37440 ALK; FAKCEP-40783 c-Met/HGFR; TAM Receptor Ceralasertib ATM/ATR CerdulatinibJAK; Syk Cerdulatinib (PRT062070, PRT2070) JAK Ceritinib ALK; IGF-1R;Insulin Receptor Ceritinib dihydrochloride ALK; IGF-1R; Insulin ReceptorCFI-400945 PLK CFI-402257 hydrochloride Mps1 cFMS Receptor Inhibitor IIc-Fms c-Fms-IN-2 c-Fms CG-806 Btk; FLT3 CGI1746 BTK CGI-1746 Autophagy;Btk CGK 733 ATM/ATR CGK733 ATM/ATR CGP 57380 MNK CGP60474 PKC; VEGFRCH5132799 PI3K CH5183284 FGFR CH5183284 (Debio-1347) FGFR CH7057288 TrkReceptor Chelerythrine Chloride Autophagy; PKC CHIR-124 Chk CHIR-98014GSK-3 CHIR-99021 Autophagy; GSK-3 CHIR-99021 (CT99021) GSK-3 Chk2Inhibitor II (BML-277) Chk Chloropyramine hydrochloride FAK; HistamineReceptor; VEGFR CHMFL-BMX-078 BMX Kinase CHR-6494 Haspin Kinase Chroman1 ROCK Chrysophanic Acid EGFR,mTOR CHZ868 JAK CI-1040 MEK CID 2011756Serine/threonin kina CID755673 Serine/threonin kinase,CaMK CK1-IN-1Casein Kinase c-Kit-IN-1 c-Kit; c-Met/HGFR CL-387785 EGFR CL-387785(EKI-785) EGFR CLK1-IN-1 CDK c-Met inhibitor 1 c-Met/HGFR CNX-2006 EGFRCNX-774 Btk Cobimetinib MEK Cobimetinib (GDC-0973, RG7420) MEKCobimetinib (hemifumarate) MEK Cobimetinib (racemate) MEK Compound 401DNA-PK Corynoxeine ERK½ CP21R7 GSK-3 CP21R7 (CP21) Wnt/beta-cateninCP-466722 ATM/ATR CP-673451 PDGFR CP-724714 EGFR,HER2 CrenolanibAutophagy; FLT3; PDGFR Crizotinib ALK; Autophagy; c-Met/HGFR CRT0066101Serine/threonin kinase,CaMK CRT0066101 dihydrochloride PKD CT7001hydrochloride CDK Cucurbitacin E Autophagy; CDK Cucurbitacin I JAK; STATCUDC-101 EGFR,HDAC,HER2 CUDC-907 HDAC,PI3K CVT-313 CDK CX-6258 PimCyasterone EGFR CYC065 CDK CYC116 Aurora Kinase,VEGFR CZ415 mTORCZC24832 PI3K CZC-25146 LRRK2 CZC-54252 LRRK2 CZC-8004 Bcr-Abl D 4476Casein Kinase D4476 Autophagy; Casein Kinase Dabrafenib Raf Dabrafenib(GSK2118436) Raf Dabrafenib (Mesylate) Raf Dabrafenib Mesylate RafDacomitinib EGFR Dacomitinib (PF299804, PF299) EGFR Dactolisib(Tosylate) Autophagy; mTOR; PI3K Danthron AMPK Danusertib Aurora Kinase;Autophagy Danusertib (PHA-739358) Aurora Kinase,Ber-Abl,c-RET,FGFRDaphnetin PKA,EGFR,PKC Dasatinib Bcr-Abl,c-Kit,Src Dasatinib MonohydrateSrc,c-Kit,Bcr-Abl DB07268 JNK DCC-2618 c-Kit DCP-LA PKC DDR1-IN-1 OthersDecernotinib (VX-509) JAK Defactinib FAK Degrasyn Autophagy; Bcr-Abl;Deubiquitinase Deguelin Akt,PI3K Dehydrocorydaline (chloride) p38 MAPKDehydrocostus Lactone IκB/IKK DEL-22379 ERK Delcasertib PKC DelgocitinibJAK Derazantinib FGFR Derazantinib(ARQ-087) FGFR Dicoumarol PDHK Dihexac-Met/HGFR Dihydromyricetin Autophagy; mTOR Dilmapimod p38 MAPKDinaciclib CDK Dinaciclib (SCH727965) CDK DMAT Casein Kinase DMH1TGF-beta/Smad DMH-1 Autophagy; TGF-β Receptor Doramapimod p38 MAPK; RafDoramapimod (BIRB 796) P38 MAPK Dorsomorphin (Compound C) AMPKDorsomorphin (dihydrochloride) AMPK; Autophagy; TGF-β Receptor Dovitinibc-Kit; FGFR; FLT3; PDGFR; VEGFR Dovitinib (lactate) FGFR Dovitinib(TKI-258) Dilactic Acid c-Kit,FGFR,FLT3,PDGFR,VEGFR Dovitinib (TKI258)Lactate FLT3,c-Kit,FGFR,PDGFR,VEGFR Dovitinib (TKI-258, CHIR-258)c-Kit,FGFR,FLT3,PDGFR,VEGFR DPH Bcr-Abl Dubermatinib TAM ReceptorDuvelisib PI3K Duvelisib (R enantiomer) PI3K EAI045 EGFR eCF506 SrcEdicotinib c-Fms eFT-508 (eFT508) MNK EG00229 VEGFR EGFR-IN-3 EGFREllagic acid Topoisomerase EMD638683 SGK EMD638683 (R-Form) SGKEMD638683 (S-Form) SGK Emodin Autophagy; Casein Kinase Empesertib Mps1Encorafenib Raf ENMD-2076 Aurora Kinase,FLT3,VEGFR ENMD-2076L-(+)-Tartaric acid Aurora Kinase,FLT3,VEGFR Entospletinib SykEntospletinib (GS-9973) Syk Entrectinib ALK; Autophagy; ROS; TrkReceptor Entrectinib (RXDX-101) Trk receptor,ALK Enzastaurin Autophagy;PKC Enzastaurin (LY317615) PKC Erdafitinib FGFR Erdafitinib(JNJ-42756493) FGFR ERK5-IN-1 ERK Erlotinib EGFR ETC-1002 AMPK; ATPCitrate Lyase ETC-206 MNK ETP-46321 PI3K ETP-46464 ATM/ATR,mTOREverolimus (RAD001) mTOR Evobrutinib Btk EX229 AMPK Falnidamol EGFRFasudil (Hydrochloride) Autophagy; PKA; ROCK Fedratinib JAK FenebrutinibBtk Ferulic acid FGFR Ferulic acid methyl ester p38 MAPK FGF401 FGFRFGFR4-IN-1 FGFR FIIN-2 FGFR FIIN-3 EGFR; FGFR Filgotinib JAK Filgotinib(GLPG0634) JAK Fimepinostat HDAC; PI3K Fingolimod LPL Receptor; PAKFisogatinib FGFR Flavopiridol Autophagy; CDK FLLL32 JAK FLT3-IN-1 FLT3FLT3-IN-2 FLT3 Flufenamic acid AMPK; Calcium Channel; Chloride Channel;COX; Potassium Channel Flumatinib Bcr-Abl; c-Kit; PDGFR Flumatinib(mesylate) Bcr-Abl; c-Kit; PDGFR FM381 JAK FM-381 JAK FMK Ribosomal S6Kinase (RSK) FN-1501 CDK; FLT3 Foretinib c-Met/HGFR; VEGFR Foretinib(GSK1363089) c-Met,VEGFR Formononetin Others Fostamatinib (R788) Syk FR180204 ERK FRAX1036 PAK FRAX486 PAK FRAX597 PAK Fruquintinib VEGFRsFutibatinib FGFR G-5555 PAK G-749 FLT3 Galunisertib TGF-β ReceptorGambogenic acid Others Gandotinib FGFR; FLT3; JAK; VEGFR Gandotinib(LY2784544) JAK GDC-0077 PI3K GDC-0084 PI3K,mTOR GDC-0326 PI3K GDC-0339Pim GDC-0349 mTOR GDC-0575 (ARRY-575, RG7741) Chk GDC-0623 MEK GDC-0834Btk GDC-0834 (Racemate) Btk GDC-0834 (S-enantiomer) Btk GDC-0879 RafGedatolisib (PF-05212384, PKI-587) mTOR,PI3K Gefitinib Autophagy; EGFRGefitinib (ZD1839) EGFR Genistein EGFR,Topoisomerase Gilteritinib(ASP2215) FLT3,TAM Receptor Ginkgolide C AMPK; MMP; Sirtuin GinsenosideRb1 Autophagy; IRAK; Mitophagy; Na+/K+ ATPase; NF-κB Ginsenoside ReAmyloid-β; JNK; NF-κB Glesatinib (hydrochloride) c-Met/HGFR; TAMReceptor GLPG0634 analog JAK GNE-0877 LRRK2 GNE-317 PI3K GNE-477 mTOR;PI3K GNE-493 mTOR; PI3K GNE-7915 LRRK2 GNE-9605 LRRK2 GNF-2 Bcr-AblGNF-5 Bcr-Abl GNF-5837 Trk Receptor GNF-7 Bcr-Abl Go 6983 PKC G06976FLT3,JAK,PKC Golvatinib (E7050) c-Met,VEGFR GSK 3 Inhibitor IX CDK;GSK-3 GSK 650394 SGK GSK1059615 mTOR,PI3K GSK1070916 Aurora KinaseGSK180736A ROCK GSK180736A (GSK180736) ROCK GSK1838705A ALK,IGF-1RGSK1904529A IGF-1R GSK2110183 (hydrochloride) Akt GSK2256098 FAKGSK2292767 PI3K GSK2334470 PDK GSK2578215A LRRK2 GSK2606414 PERKGSK2636771 PI3K GSK2656157 PERK GSK269962A ROCK GSK2850163 IRE1GSK2982772 TNF-alpha,NF-κB GSK-3 inhibitor 1 GSK-3 GSK429286A ROCKGSK461364 PLK GSK48 TNF-alpha GSK′481 RIP kinase GSK′547 TNF-alphaGSK583 NF-κB GSK650394 Others GSK690693 Akt GSK-872 RIP kinase GSK′963NF-κB,TNF-alpha Gusacitinib JAK; Syk GW441756 Trk Receptor GW5074 RafGW2580 CSF-1R GW441756 Trk receptor GW5074 Raf GW788388 TGF-beta/SmadGW843682X Polo-like Kinase (PLK) GZD824 Ber-Abl GZD824 DimesylateBer-Abl H3B-6527 FGFR H-89 (dihydrochloride) Autophagy; PKA HA-100Myosin; PKA; PKC Harmine 5-HT Receptor; DYRK; RAD51 Harminehydrochloride DYRK HER2-Inhibitor-1 EGFR,HER2 Hesperadin Aurora KinaseHG-10-102-01 LRRK2 HG-14-10-04 ALK HG6-64-1 Raf HG-9-91-01Salt-inducible Kinase (SIK) Hispidulin Pim HMN-214 PLK Honokiol Akt,MEKHS-10296 hydrochloride EGFR HS-1371 Serine/threonin kina HS-173 PI3KHTH-01-015 AMPK hVEGF-IN-1 VEGFR Hydroxyfasudil ROCK Ibrutinib BtkIbrutinib (PCI-32765) BTK IC261 Casein Kinase IC-87114 PI3K IcotinibEGFR ID-8 DYRK Idelalisib Autophagy; PI3K Idelalisib (CAL-101, GS-1101)PI3K IITZ-01 Autophagy; PI3K IKK 16 IKK; LRRK2 IKK-IN-1 IKK IlginatinibJAK IM-12 GSK-3 Imatinib Autophagy; Ber-Abl; c-Kit; PDGFR ImatinibMesylate (STI571) Bcr-Abl,c-Kit,PDGFR IMD 0354 IκB/IKK IMD-0354 IKKIMD-0560 IKK INCB053914 (phosphate) Pim Indirubin GSK-3Indirubin-3′-monoxime 5-Lipoxygenase; GSK-3 Infigratinib FGFR IngenolPKC INH14 IKK IPA-3 PAK Ipatasertib Akt IPI-3063 PI3K IPI549 PI3KIPI-549 PI3K IQ-1S (free acid) JNK IRAK inhibitor 1 IRAK IRAK inhibitor2 IRAK IRAK inhibitor 4 (trans) IRAK IRAK inhibitor 6 IRAK IRAK-1-4Inhibitor I IRAK IRAK4-IN-1 IRAK Irbinitinib (ARRY-380, ONT-380) HER2ISCKo3 c-Kit Isorhamnetin MEK; PI3K Isorhamnetin 3-O-neohesperosideOthers Isovitexin JNK; NF-κB ISRIB (trans-isomer) PERK Itacitinib JAKITD-1 TGF-β Receptor ITX5061 p38 MAPK JAK3-IN-1 JAK JANEX-1 JAKJH-II-127 LRRK2 JH-VIII-157-02 ALK JI-101 Ephrin Receptor; PDGFR; VEGFRJNJ-38877605 c-Met JNJ-38877618 c-Met/HGFR JNJ-47117096 hydrochlorideFLT3; MELK JNJ-7706621 Aurora Kinase,CDK JNK Inhibitor IX JNK JNK-IN-7JNK JNK-IN-8 JNK K02288 TGF-beta/Smad K03861 CDK K145 (hydrochloride)SPHK kb NB 142-70 PKD KD025 (SLx-2119) ROCK KDU691 PI4K Kenpaullone CDKKi20227 c-Fms Ki8751 c-Kit,PDGFR,VEGFR kira6 ^(Others) KN-62 CaMK KN-92(hydrochloride) CaMK KN-93 CaMK KN-93 Phosphate CaMK KPT-9274 NAMPT,PAKKRN 633 VEGFR KU-0063794 mTOR KU-55933 ATM/ATR; Autophagy KU-57788CRISPR/Cas9; DNA-PK KU-60019 ATM/ATR KW-2449 Aurora Kinase,Ber-Abl,FLT3KX1-004 Src KX2-391 Src L-779450 Autophagy; Raf Lapatinib EGFR,HER2Larotrectinib (LOXO-101) sulfate Trk receptor Larotrectinib sulfate TrkReceptor Lazertinib EGFR Lazertinib (YH25448,GNS-1480) EGFR LckInhibitor Src Lck inhibitor 2 Src LDC000067 CDK LDC1267 TAM ReceptorLDC4297 CDK LDN-193189 2HCl TGF-beta/Smad LDN-212854 TGF-β ReceptorLDN-214117 TGF-beta/Smad Leflunomide Dehydrogenase Leniolisib PI3KLenvatinib VEGFR Lerociclib dihydrochloride CDK LFM-A13 BTK LifirafenibEGFR; Raf Linifanib Autophagy; FLT3; PDGFR; VEGFR Linsitinib IGF-1R;Insulin Receptor LJH685 S6 Kinase LJI308 S6 Kinase L-Leucine mTORLM22A-4 Trk Receptor LM22B-10 Akt; ERK; Trk Receptor Longdaysin CaseinKinase; ERK Lonidamine Hexokinase Lorlatinib ALK Lorlatinib?(PF-6463922)ALK Losmapimod Autophagy; p38 MAPK Losmapimod (GW856553X) p38 MAPKLoureirin B ERK; JNK; PAI-1; Potassium Channel LRRK2 inhibitor 1 LRRK2LRRK2-IN-1 LRRK2 LSKL, Inhibitor of Thrombospondin TGF-β Receptor(TSP-1) LTURM34 DNA-PK Lucitanib FGFR; VEGFR Lupeol Immunology &Inflammation related LX2343 Amyloid-β; Autophagy; Beta-secretase; PI3KLXH254 Raf LXS196 PKC LY2090314 GSK-3 LY2109761 TGF-beta/Smad LY2409881IκB/IKK LY2584702 S6 Kinase LY2584702 Tosylate S6 Kinase LY2608204Glucokinase LY2857785 CDK LY2874455 FGFR,VEGFR LY294002 Autophagy,PI3KLY3009120 Raf LY3023414 mTOR,PI3K,DNA-PK LY3177833 CDK LY3200882 TGF-βReceptor LY3214996 ERK LY3295668 Aurora Kinase LY364947 TGF-beta/SmadLY-364947 TGF-β Receptor LYN-1604 hydrochloride ULK Magnolin ERK1Masitinib c-Kit; PDGFR MBQ-167 CDK; Ras MC180295 CDK MCB-613 Src MEKinhibitor MEK MELK-8a (hydrochloride) MELK Merestinib c-Met/HGFRMesalamine IκB/IKK,Immunology & Inflammation related Metadoxine PKAMetformin (hydrochloride) AMPK; Autophagy; Mitophagy MethylthiouracilERK; Interleukin Related; NF-κB; TNF Receptor MGCD-265 analogc-Met/HGFR; VEGFR MHP SPHK MHY1485 Autophagy; mTOR Midostaurin PKCMilciclib (PHA-848125) CDK Miltefosine Akt Miransertib Akt Mirin ATM/ATRMirk-IN-1 DYRK Mitoxantrone PKC; Topoisomerase MK 2206 (dihydrochloride)Akt; Autophagy MK-2461 c-Met,FGFR,PDGFR MK2-IN-1 (hydrochloride)MAPKAPK2 (MK2) MK-3903 AMPK MK-5108 Aurora Kinase MK-8033 c-Met/HGFRMK8722 AMPK MK-8745 Aurora Kinase MK-8776 (SCH 900776) CDK,Chk MKC3946IRE1 MKC8866 IRE1 MKC9989 IRE1 ML167 CDK ML347 TGF-beta/Smad,ALK ML-7HC1 Serine/threonin kinase MLi-2 LRRK2 MLN0905 PLK MLN120B IKK MLN2480Raf MLN8054 Aurora Kinase MNS Src; Syk MNS (3,4-Methylenedioxy-β-Tyrosinase,p97,Syk,Src nitrostyrene, MDBN) Momelotinib Autophagy; JAKMotesanib c-Kit; VEGFR MP7 PDK-1 MP-A08 SPHK MPI-0479605 KinesinMps1-IN-1 Mps1 Mps1-IN-2 Mps1; Polo-like Kinase (PLK) MRT67307 HClIκB/IKK MRT68921 (hydrochloride) ULK MRX-2843 FLT3 MSC2530818 CDK MSDC0160 Insulin Receptor mTOR inhibitor-3 mTOR MTX-211 EGFR; PI3KMubritinib EGFR Mutated EGFR-IN-1 EGFR Myricetin MEK NAMI-A FAKNaquotinib(ASP8273) EGFR Narciclasine ROCK Nazartinib EGFR Nazartinib(EGF816, NVS-816) EGFR NCB-0846 Wnt/beta-catenin Nec-1s (7-Cl-O-Nec1)TNF-alpha Necrostatin-1 Autophagy; RIP kinase Necrosulfonamide OthersNedisertib DNA-PK Neflamapimod p38 MAPK Nemiralisib PI3K Neohesperidindihydrochalcone ROS Neratinib (HKI-272) EGFR,HER2 NG 52 CDK NH125 CaMKNilotinib Autophagy; Ber-Abl Nilotinib (AMN-107) Ber-Abl Ningetinibc-Met/HGFR; TAM Receptor; VEGFR Nintedanib FGFR; PDGFR; VEGFR NMS-P937(NMS1286937) PLK Nocodazole Autophagy,Microtubule AssociatedNorcantharidin EGFR,c-Met Notoginsenoside R1 Others NPS-1034 c-Met,TAMReceptor NQDI-1 ASK NSC 228155 EGFR; Epigenetic Reader Domain; HistoneAcetyltransferase NSC 42834 JAK NSC12 FGFR NSC781406 mTOR; PI3K NT157IGF-1R NU 7026 DNA-PK NU2058 CDK NU6027 CDK NU6300 CDK NU7026 DNA-PKNU7441 (KU-57788) DNA-PK,PI3K NVP-2 CDK NVP-ACC789 PDGFR; VEGFRNVP-ADW742 IGF-1R NVP-BAW2881 VEGFR NVP-BHG712 Ber-Abl,Ephrinreceptor,Raf,Src NVP-BHG712 isomer Ephrin Receptor NVP-BSK805 2HCl JAKNVP-BVU972 c-Met NVP-LCQ195 CDK NVP-TAE 226 FAK; Pyk2 NVP-TAE 684 ALKNVS-PAK1-1 PAK Oclacitinib (maleate) JAK Oglufanide VEGFR Olmutinib EGFROmipalisib mTOR; PI3K Omtriptolide ERK ON123300 CDK ONO-4059 (GS-4059)hydrochloride BTK Orantinib (TSU-68, SU6668) PDGFR Oridonin Akt OSI-027mTOR OSI-420 EGFR OSI-930 c-Kit,CSF-1R,VEGFR Osimertinib EGFR OSU-03012(AR-12) PDK OTS514 hydrochloride TOPK OTS964 TOPK OTSSP167(hydrochloride) MELK P276-00 CDK p38α inhibitor 1 p38 MAPK p38-αMAPK-IN-1 p38 MAPK Pacritinib FLT3; JAK Palbociclib (hydrochloride) CDKPalbociclib (isethionate) CDK Palomid 529 mTOR Palomid 529 (P529) mTORPamapimod p38 MAPK Parsaclisib PI3K Pazopanib c-Kit,PDGFR,VEGFR PCI29732 Btk PCI-33380 Btk PD 169316 Autophagy; p38 MAPK PD0166285 Wee1PD0325901 MEK PD153035 EGFR PD158780 EGFR PD-166866 FGFR PD168393 EGFRPD173074 FGFR,VEGFR PD173955 Bcr-Abl PD184352 (CI-1040) MEK PD318088 MEKPD98059 MEK Peficitinib JAK Pelitinib EGFR; Src Pelitinib (EKB-569) EGFRPemigatinib FGFR Perifosine (KRX-0401) Akt Pexidartinib c-Fms; c-KitPexmetinib (ARRY-614) p38 MAPK,Tie-2 PF-00562271 Besylate FAKPF-03814735 Aurora Kinase; VEGFR PF-04217903 c-Met PF-04217903(methanesulfonate) c-Met/HGFR PF-04691502 Akt,mTOR,PI3K PF-04965842 JAKPF-05231023 FGFR PF-06273340 Trk receptor PF-06409577 AMPK PF-06447475LRRK₂ PF-06459988 EGFR PF06650833 IRAK PF-06651600 JAK PF-06700841(P-Tosylate) JAK PF-3758309 PAK PF-431396 FAK PF-4708671 S6 KinasePF-477736 Chk PF-4800567 Casein Kinase PF-4989216 PI3K PF-543 (Citrate)SPHK PF-562271 FAK PF-573228 FAK PFK15 Autophagy PFK158 AutophagyPH-797804 p38 MAPK PHA-665752 c-Met PHA-680632 Aurora Kinase PHA-767491CDK PHA-793887 CDK Phenformin (hydrochloride) AMPK Phorbol 12-myristate13-acetate PKC; SPHK PHT-427 Akt,PDK PI-103 Autophagy,DNA-PK,mTOR,PI3KPI-103 (Hydrochloride) DNA-PK; mTOR; PI3K PI-3065 PI3K PI3K-IN-1 PI3KPI3Kδ-IN-2 PI3K PI4KIII beta inhibitor 3 PI4K Piceatannol SykPicfeltarraenin IA AChE Picropodophyllin IGF-1R Pictilisib (GDC-0941)PI3K PIK-293 PI3K PIK-294 PI3K PIK-75 DNA-PK; PI3K PIK-75 HC1DNA-PK,PI3K PIK-93 PI3K PIK-III Autophagy,PI3K Pilaralisib PI3KPilaralisib analogue PI3K Pim1/AKK1-IN-1 Pim PIM-447 (dihydrochloride)Pim Pimasertib MEK Pitavastatin Calcium HMG-CoA Reductase PKC-IN-1 PKCPKC-theta inhibitor PKC PKM2 inhibitor(compound 3k) PKM Pluripotin ERK;Ribosomal S6 Kinase (RSK) PLX-4720 Raf PLX647 c-Fms; c-Kit PLX7904 RafPLX8394 Raf PND-1186 FAK PND-1186 (VS-4718) FAK Poloxime Polo-likeKinase (PLK) Poloxin Polo-like Kinase (PLK) Ponatinib (AP24534)Bcr-Abl,FGFR,PDGFR,VEGFR Poziotinib (HM781-36B) HER2,EGFR PP1 Src PP121DNA-PK,mTOR,PDGFR,Src,VEGFR,Ber-Abl PP2 Src PQ 401 IGF-1R PQR620 mTORPrexasertib Checkpoint Kinase (Chk) PRN1008 Btk PRN1371 FGFR PRN694 ItkPROTAC CDK9 Degrader-1 CDK; PROTAC Protein kinase inhibitors 1 DYRKhydrochloride PRT-060318 Syk PRT062607 (Hydrochloride) Syk PS-1145IκB/IKK Psoralidin Estrogen/progestogen Receptor Purvalanol A CDKPurvalanol B CDK PYR-41 E1 Activating Pyridone 6 JAK Pyrotinib dimaleateEGFR Quercetin Src,Sirtuin,PKC,PI3K Quizartinib (AC220) FLT3 R112 SykR1487 (Hydrochloride) p38 MAPK R1530 VEGFR R-268712 TGF-β Receptor R406FLT3,Syk R406 (free base) Syk R547 CDK R788 (Fostamatinib) Disodium SykRabusertib (LY2603618) Chk Radotinib Ber-Abl RAF265 Autophagy; Raf;VEGFR RAF265 (CHIR-265) Raf,VEGFR RAF709 Raf Ralimetinib (LY2228820) p38MAPK Rapamycin (Sirolimus) Autophagy,mTOR Ravoxertinib ERK RebastinibBcr-Abl; FLT3; Src Refametinib MEK Refametinib (RDEA119, Bay 86-9766)MEK Regorafenib Autophagy; PDGFR; Raf; VEGFR Repotrectinib ALK; ROS; TrkReceptor RepSox TGF-beta/Smad Resveratrol Autophagy; IKK; Mitophagy;Sirtuin Reversine Adenosine Receptor,Aurora Kinase RG13022 EGFR RG14620EGFR RGB-286638 (free base) CDK; GSK-3; JAK; MEK Ribociclib CDKRidaforolimus (Deforolimus, MK- mTOR 8669) Rigosertib (ON-01910) PLKRigosertib (sodium) Polo-like Kinase (PLK) Rimacalib CaMK RIP2 kinaseinhibitor 1 RIP kinase RIP2 kinase inhibitor 2 RIP kinase RIPA-56 RIPkinase Ripasudil ROCK Ripretinib c-Kit; PDGFR RK-24466 Src RKI-1447 ROCKRN486 Btk R028-1675 Glucokinase R05126766 MEK; Raf R03280 PLK R0-3306CDK RO4987655 MEK RO9021 Syk Roblitinib FGFR Rociletinib EGFRRociletinib (CO-1686, AVL-301) EGFR Rociletinib hydrobromide EGFRRogaratinib FGFR Roscovitine (Seliciclib,CYC202) CDK Rosmarinic acidIκB/IKK Ruboxistaurin (LY333531 HCl) PKC Ruxolitinib Autophagy; JAK;Mitophagy Ruxolitinib (phosphate) Autophagy; JAK; Mitophagy Ruxolitinib(S enantiomer) Autophagy; JAK RXDX-106 (CEP-40783) TAM Receptor S49076c-Met,FGFR,TAM Receptor SAFit2 Akt Salidroside mTOR Salubrinal PERKSapanisertib Autophagy; mTOR Sapitinib EGFR SAR-020106 Chk SAR125844c-Met SAR131675 VEGFR SAR-20347 JAK SAR-260301 PI3K SAR405 Autophagy;PI3K SAR407899 ROCK Saracatinib Autophagy; Src Saracatinib (AZD0530) SrcSavolitinib c-Met/HGFR Savolitinib(AZD6094, HMPL-504) c-Met SB 202190Autophagy; p38 MAPK SB 203580 Autophagy; Mitophagy; p38 MAPK SB 203580(hydrochloride) Autophagy; Mitophagy; p38 MAPK SB 239063 p38 MAPK SB242235 p38 MAPK SB 415286 GSK-3 SB 525334 TGF-β Receptor SB1317 CDK;FLT3; JAK SB202190 (FHPI) p38 MAPK SB203580 p38 MAPK SB216763 GSK-3SB239063 p38 MAPK SB415286 GSK-3 SB431542 TGF-beta/Smad SB-431542 TGF-βReceptor SB505124 TGF-beta/Smad SB-505124 TGF-β Receptor SB525334TGF-beta/Smad SB590885 Raf SB-590885 Raf SBE 13 HCl PLK SBI-0206965Autophagy SC-514 IκB/IKK SC66 Akt SC79 Akt SCH-1473759 (hydrochloride)Aurora Kinase SCH772984 ERK SCH900776 Checkpoint Kinase (Chk)Schisandrin B (Sch B) ATM/ATR,P-gp Scopoletin Immunology & Inflammationrelated SCR-1481B1 e-Met/HGFR; VEGFR Scutellarein Autophagy; SrcScutellarin Akt; STAT SD 0006 p38 MAPK SD-208 TGF-beta/Smad SEL120-34A(monohydrochloride) CDK Seletalisib PI3K Seletalisib (UCB-5857) PI3KSeliciclib CDK Selitrectinib Trk Receptor Selonsertib (GS-4997) ASKSelumetinib MEK Selumetinib (AZD6244) MEK Semaxanib (SU5416) VEGFRSemaxinib VEGFR Senexin A CDK Sennoside B PDGFR Serabelisib PI3KSerabelisib (INK-1117,MLN-1117,TAK-117) PI3K SF1670 PTEN SF2523PI3K,DNA-PK,Epigenetic Reader Domain,mTOR SGI-1776 Autophagy; PimSGI-1776 free base Pim SGI-7079 VEGFR SGX-523 c-Met SilmitasertibAutophagy; Casein Kinase Simurosertib CDK Sitravatinib c-Kit; DiscoidinDomain Receptor; FLT3; Trk Receptor; VEGFR Sitravatinib (MGCD516) Ephrinreceptor,c-Kit,TAM Receptor,VEGFR,Trk receptor SJ000291942 TGF-βReceptor SK1-IN-1 SPHK Skatole Aryl Hydrocarbon Receptor; p38 MAPKSkepinone-L p38 MAPK SKF-86002 p38 MAPK SKI II S1P Receptor SKLB1002VEGFR SKLB4771 FLT3 SL327 MEK SL-327 MEK SLV-2436 MNK SLx-2119 ROCK SM16 TGF-β Receptor SMI-16a Pim SMI-4a Pim SNS-032 CDK SNS-032(BMS-387032) CDK SNS-314 Aurora Kinase SNS-314 Mesylate Aurora KinaseSodium dichloroacetate (DCA) Dehydrogenase Sodium Monofluorophosphatephosphatase Solanesol (Nonaisoprenol) FAK Solcitinib JAK Sorafenib RafSorafenib Tosylate PDGFR,Raf,VEGFR Sotrastaurin PKC SP600125 JNKSpebrutinib Btk SPHINX31 Serine/threonin kina SR-3029 Casein KinaseSR-3306 JNK SR-3677 Autophagy; ROCK Src Inhibitor 1 Src SRPIN340 SRPKS-Ruxolitinib (INCB018424) JAK SSR128129E FGFR Staurosporine PKA; PKCSTF-083010 IRE1 STO-609 CaMK SU 5402 FGFR; PDGFR; VEGFR SU11274 c-MetSU14813 c-Kit; PDGFR; VEGFR SU14813 (maleate) c-Kit; PDGFR; VEGFR SU1498VEGFR SU5402 FGFR,VEGFR SU5408 VEGFR SU6656 Src SU9516 CDK SulfatinibFGFR; VEGFR SUN11602 FGFR Sunitinib PDGFR,c-Kit,VEGFR Sunitinib Malatec-Kit,PDGFR,VEGFR T56-LIMKi LIM Kinase (LIMK) TA-01 Casein Kinase; p38MAPK TA-02 p38 MAPK TAE226 (NVP-TAE226) FAK TAE684 (NVP-TAE684) ALKTAK-285 EGFR,HER2 TAK-580 Raf TAK-593 PDGFR; VEGFR TAK-632 Raf TAK-659Syk,FLT3 TAK-715 p38 MAPK TAK-733 MEK TAK-901 Aurora Kinase TAK-960Polo-like Kinase (PLK) Takinib IL Receptor Talmapimod p38 MAPKTandutinib FLT₃ Tandutinib (MLN518) FLT3 Tanzisertib JNKTanzisertib(CC-930) JNK tarloxotinib bromide EGFR TAS-115 mesylatec-Met/HGFR; VEGFR TAS-301 PKC TAS6417 EGFR Taselisib PI3K Tat-NR2B9c p38MAPK Tat-NR2B9c (TFA) p38 MAPK Tauroursodeoxycholate (Sodium) Caspase;ERK Tauroursodeoxycholate dihydrate Caspase; ERK Taxifolin(Dihydroquercetin) VEGFR TBB Casein Kinase TBK1/IKKε-IN-2 IKK TC13172Mixed Lineage Kinase TC-DAPK 6 DAPK TCS 359 FLT3 TCS JNK 5a JNK TCSPIM-11 Pim TCS-PIM-1-4a Pim TDZD-8 GSK-3 Telatinib c-Kit,PDGFR,VEGFRTemsirolimus (CCI-779, NSC 683864) mTOR Tenalisib PI3K Tenalisib(RP6530) PI3K Tepotinib Autophagy; c-Met/HGFR Tepotinib (EMD 1214063)c-Met TG 100572 (Hydrochloride) FGFR; PDGFR; Src; VEGFR TG003 CDKTG100-115 PI3K TG100713 PI3K TG101209 c-RET,FLT3,JAK TGX-221 PI3KTheliatinib (HMPL-309) EGFR Thiazovivin ROCK THZ1 CDK THZ1-R CDK THZ2CDK THZ531 CDK TIC10 Akt TIC10 Analogue Akt Tideglusib GSK-3 Tie2 kinaseinhibitor Tie-2 Tirabrutinib Btk Tirbanibulin (Mesylate)Microtubule/Tubulin; Src Tivantinib c-Met/HGFR Tivantinib (ARQ 197)c-Met Tivozanib VEGFR Tivozanib (AV-951) c-Kit,PDGFR,VEGFR Toceranibphosphate PDGFRβ Tofacitinib JAK Tofacitinib (CP-690550,Tasocitinib) JAKTolimidone Src Tomivosertib MNK Torin 1 Autophagy,mTOR Torin 2ATM/ATR,mTOR Torkinib Autophagy; Mitophagy; mTOR Tozasertib (VX-680,MK-0457) Aurora Kinase TP0427736 HCl ALK TP-0903 TAM Receptor TP-3654Pim TPCA-1 IκB/IKK TPPB PKC TPX-0005 Src,ALK Trametinib MEK trans-ZeatinERK; MEK Trapidil PDGFR Triciribine Akt TTP 22 Casein Kinase TucatinibEGFR TWS119 GSK-3 TyK2-IN-2 JAK Tyk2-IN-4 JAK Tyrosine kinase inhibitorc-Met/HGFR Tyrosine kinase-IN-1 FGFR; PDGFR; VEGFR Tyrphostin 23 EGFRTyrphostin 9 PDGFR,EGFR Tyrphostin A9 VEGFR Tyrphostin AG 1296c-Kit,PDGFR Tyrphostin AG 528 EGFR Tyrphostin AG 879 HER2 U0126Autophagy; MEK; Mitophagy U0126-EtOH MEK UCB9608 PI4K UK-371804 HClSerine Protease Ulixertinib ERK ULK-101 ULK UM-164 Src,p38 MAPKUmbralisib PI3K Umbralisib R-enantiomer PI3K UNC2025 TAM Receptor,FLT3UNC2881 TAM Receptor Upadacitinib JAK Uprosertib Akt URMC-099 LRRK2Vactosertib TGF-β Receptor Vactosertib (Hydrochloride) TGF-β ReceptorValrubicin PKC Vandetanib Autophagy; VEGFR Varlitinib EGFR Vatalanib(PTK787) 2HCl VEGFR VE-821 ATM/ATR VE-822 ATM/ATR Vecabrutinib Btk; ItkVemurafenib Autophagy; Raf VER-246608 PDHK Verbascoside Immunology &Inflammation related Vistusertib Autophagy; mTOR Volasertib (BI 6727)PLK VO-Ohpic trihydrate PTEN Voxtalisib mTOR; PI3K VPS34 inhibitor 1(Compound 19, PIK- III analogue) PI3K Vps34-IN-1 PI3K Vps34-IN-2 PI3KVps34-PIK-III Autophagy; PI3K VS-5584 mTOR; PI3K VS-5584 (SB2343) PI3KVTX-27 PKC VX-11e ERK VX-702 p38 MAPK VX-745 p38 MAPK WAY-600 mTORWedelolactone NF-κB WEHI-345 RIP kinase WH-4-023 Src WHI-P154 EGFR; JAKWHI-P180 EGFR; VEGFR WHI-P97 JAK WNK463 Serine/threonin kinase WogoninCDK, Transferase Wortmannin ATM/ATR; DNA-PK; PI3K; Polo-like Kinase(PLK) WP1066 JAK; STAT WYE-125132 (WYE-132) mTOR WYE-132 mTOR WYE-354mTOR WZ3146 EGFR WZ-3146 EGFR WZ4002 EGFR WZ4003 AMPK WZ8040 EGFR X-376ALK; c-Met/HGFR XL019 JAK XL147 analogue PI3K XL228 Aurora Kinase;Ber-Abl; IGF-1R; Src XL388 mTOR XL413 (BMS-863233) CDK XMD16-5 ACKXMD17-109 ERK XMD8-87 ACK XMD8-92 ERK Y15 FAK Y-27632 ROCK Y-33075 ROCKY-39983 HCl ROCK YKL-05-099 Salt-inducible Kinase (SIK) YLF-466D AMPKYM-201636 Autophagy; PI₃K; PIKfyve YU238259 DNA-PK Zanubrutinib BtkZD-4190 EGFR; VEGFR ZINC00881524 ROCK ZINC00881524 (ROCK inhibitor) ROCKZLN024 (hydrochloride) AMPK ZM 306416 VEGFR ZM 323881 HCl VEGFR ZM336372 Raf ZM 39923 HCl JAK ZM 447439 Aurora Kinase ZM39923(hydrochloride) JAK ZM-447439 Aurora Kinase Zotarolimus(ABT-578) mTORZSTK474 PI3K

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The features of the present invention disclosed in the specification,the claims, and/or in the accompanying figures may, both separately andin any combination thereof, be material for realizing the invention invarious forms thereof.

1. A method of identifying a targeted therapy compound selected fromprotein kinase inhibitors, small molecule inhibitors, and monoclonalantibody-based compounds for personalized medicine, comprising, in anyorder, the following steps: a) obtaining a tumor sample from a patient,b) optionally, determining a level of phosphorylated TTP in said tumorsample, c) providing one or more targeted therapy compound(s) to betested, d) treating said tumor sample with said one or more targetedtherapy compound(s), e) determining whether said one or more targetedtherapy compound(s) reduce(s) the levels of phosphorylated TTP in saidtreated sample compared to a control, wherein a reduction in the levelof phosphorylated TTP indicates that said one or more targeted therapycompound(s) is/are effective for treating said patient.
 2. The method,according to claim 1, wherein said targeted therapy compound is forprecision cancer therapy of a cancer patient.
 3. The method according toclaim 1, wherein said control in step e) is a level of phosphorylatedTTP determined in step b), and/or is a reference value, and/or is alevel of phosphorylated TTP determined in a reference sample.
 4. Themethod according to claim 1, wherein said reduction is a reduction by atleast 15%.
 5. The method, according to claim 4, wherein said reductionis a reduction by at least 25%.
 6. The method according to claim 1,wherein said level of phosphorylated TTP is determined using an antibodyor antigen-binding fragment thereof targeting phosphorylated TTP.
 7. Themethod according to claim 1, wherein said targeted therapy is capable oftreating a cancer regardless of the tissue type or subtype or molecularsub-type of the cancer including solid tumors, hematological tumors,leukemias, lymphomas, organ-specific tumors such as breast, colon,prostate, liver, and metastatic tumors of any origin, including subtypeshormone positive, hormone negative, Microsatellite Instability high orlow, KRAS mutant, p53 mutant cancer, and cancers with amplified genes.